RESUMO
ABSTRACT: The role of intravenous immunoglobulin in protecting the diabetic heart from ischemia/reperfusion (I/R) injury is unclear. Hearts isolated from adult diabetic and nondiabetic Wistar rats (n = 8 per group) were treated with intravenous immunoglobulin (IVIG) either 2 hours before euthanasia, before ischemia, or at reperfusion. Hemodynamic data were acquired using the Isoheart software version 1.524-S. Ischemia/reperfusion (I/R) injury was evaluated by 2,3,5-triphenyltetrazolium chloride staining and troponin T levels. The levels of apoptosis markers, caspases-3/8, antioxidant enzymes, superoxide dismutase and catalase, glucose transporters, GLUT-1 and GLUT-4, phosphorylated ERK1/2, and phosphorylated eNOS were estimated by Western blotting. Proinflammatory and anti-inflammatory cytokine levels were evaluated using enzyme-linked immunosorbent assays. Intravenous immunoglobulin administration abolished the effects of I/R injury in hearts subjected to hyperglycemia when infused at reperfusion, before ischemia, or at reperfusion in 4-week diabetic rat hearts and only at reperfusion in 6-week diabetic rat hearts. IVIG infusion resulted in a significant (P < 0.05) recovery of cardiac hemodynamics and decreased infarct size. IVIG also reduced the levels of troponin T, apoptotic enzymes, and proinflammatory cytokines. IVIG significantly (P < 0.05) increased the levels of anti-inflammatory cytokines, antioxidant enzymes, GLUT-4, and phosphorylated eNOS. Intravenous immunoglobulin protected the hearts from I/R injury if infused at reperfusion in the presence of hyperglycemia, in 4- and 6-week diabetic rat hearts, and when infused before ischemia in 4-week diabetic rat hearts. IVIG exerts its cardioprotective effects associated with the upregulated phosphorylated eNOS/GLUT-4 pathway.
Assuntos
Diabetes Mellitus Experimental , Transportador de Glucose Tipo 4 , Traumatismo por Reperfusão Miocárdica , Óxido Nítrico Sintase Tipo III , Ratos Wistar , Transdução de Sinais , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Transportador de Glucose Tipo 4/metabolismo , Masculino , Imunoglobulinas Intravenosas/farmacologia , Apoptose/efeitos dos fármacos , Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Ratos , Estresse Oxidativo/efeitos dos fármacos , Citocinas/metabolismo , Preparação de Coração Isolado , Mediadores da Inflamação/metabolismoRESUMO
Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.
Assuntos
Apoptose , Cardiomiopatias , Modelos Animais de Doenças , Metabolismo Energético , Mitocôndrias Cardíacas , Traumatismo por Reperfusão Miocárdica , Material Particulado , Transdução de Sinais , Uremia , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Material Particulado/toxicidade , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Masculino , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/fisiopatologia , Apoptose/efeitos dos fármacos , Uremia/metabolismo , Uremia/induzido quimicamente , Uremia/patologia , Uremia/complicações , Metabolismo Energético/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Poluentes Atmosféricos/toxicidade , Ratos Sprague-Dawley , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adenina/toxicidade , Adenina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/fisiopatologia , Fosfatidilinositol 3-Quinase/metabolismoRESUMO
This research focused on investigating the effects of sevoflurane (Sev) on myocardial autophagy levels after myocardial ischemia reperfusion (I/R) injury via the microRNA-542-3p (miR-542-3p)/ADAM9 axis. Mice underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by echocardiography. Cardiac markers and oxidative stress factors were evaluated by ELISA. Autophagy-associated factors were detected by western blot. Relationship between miR-542-3p and ADAM9 was tested by dual-luciferase reporter gene assay, RT-qPCR, and western blot. Sev treatment ameliorated cardiac dysfunction, myocardial oxidative stress, and histopathological damages, decreased myocardial infarction size and myocardial apoptotic cells after myocardial I/R injury. Sev treatment elevated miR-542-3p expression and decreased ADAM9 expression in myocardial tissues after myocardial I/R injury. miR-542-3p overexpression could enhance the ameliorative effects of Sev on myocardial injury and myocardial autophagy in I/R mice. miR-542-3p targeted and negatively regulated ADAM9 expression. ADAM9 overexpression reversed the ameliorative effects of miR-542-3p up-regulation on myocardial injury and myocardial autophagy in Sev-treated I/R mice. Sev treatment could ameliorate myocardial injury and myocardial autophagy in I/R mice, mediated by mechanisms that include miR-542-3p up-regulation and ADAM9 down-regulation.
Assuntos
Autofagia , Modelos Animais de Doenças , Proteínas de Membrana , Camundongos Endogâmicos C57BL , MicroRNAs , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Estresse Oxidativo , Sevoflurano , Transdução de Sinais , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Sevoflurano/farmacologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Autofagia/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas ADAM/metabolismo , Proteínas ADAM/genética , Apoptose/efeitos dos fármacos , Camundongos , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genéticaRESUMO
Chronic psychological stress is a recognized, yet understudied risk factor for heart disease, with potential sex-specific effects. We investigated whether chronic stress triggers sex-dependent cardiac dysfunction in isolated Wistar rat hearts subjected to ischemia-reperfusion injury. The experimental cohort underwent 1 h of daily restraint stress for 4 wk versus matched controls, followed by euthanasia (sodium pentobarbital) and heart excision for ex vivo perfusion. Blood analysis revealed sex-specific alterations in stress hormones and inflammatory markers. When compared with controls, chronic restraint stress (CRS) males displayed decreased plasma brain-derived neurotrophic factor (BDNF) levels (P < 0.05), whereas CRS females exhibited elevated plasma adrenocorticotropic hormone (ACTH) (P < 0.01) and reduced corticosterone (P < 0.001) alongside lower serum estradiol (P < 0.001) and estradiol/progesterone ratio (P < 0.01). Of note, CRS females showed increased serum cardiac troponin T (P < 0.05) and tumor necrosis factor-α (TNF-α) (P < 0.01) with suppressed interleukin (IL)-1α, IL-1ß, IL-6, and IL-10 levels (P < 0.05) when compared with controls. Ex vivo Langendorff perfusions revealed that CRS female hearts displayed impaired postischemic functional recovery for baseline stroke volume (SV, P < 0.01), work performance (P < 0.05), aortic output (AO, P < 0.05), coronary flow (CF, P < 0.01), and overall cardiac output (CO, P < 0.01) when compared with matched controls and CRS males (P < 0.05). Our findings reveal intriguing sex-specific responses at both the systemic and functional levels in stressed hearts. Here, the dysregulation of stress hormones, proinflammatory state, and potential underlying cardiomyopathy in females following the stress protocol renders them more prone to damage following myocardial ischemia. This study emphasizes the importance of incorporating sex as a biological variable in cardiac research focusing on stress-related cardiomyopathy.NEW & NOTEWORTHY Although chronic psychological stress is a risk factor for cardiovascular diseases, the underlying mechanisms remain poorly understood. This study revealed that chronic restraint stress resulted in systemic changes (dysregulated stress hormones, proinflammatory state) and potential cardiomyopathy in females versus controls and their male counterparts. The stressed female hearts also displayed reduced functional recovery following ex vivo ischemia-reperfusion. This highlights the importance of incorporating sex as a biological variable in cardiac research.
Assuntos
Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Estresse Psicológico , Animais , Masculino , Feminino , Estresse Psicológico/fisiopatologia , Estresse Psicológico/sangue , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Fatores Sexuais , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Função Ventricular Esquerda , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Restrição Física , Citocinas/metabolismo , Citocinas/sangue , Corticosterona/sangue , Modelos Animais de Doenças , Hormônio Adrenocorticotrópico/sangue , Coração/fisiopatologia , Coração/inervação , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/sangue , Estradiol/sangue , Miocárdio/metabolismoRESUMO
PURPOSE: Esaxerenone, a mineralocorticoid receptor blocker, attenuates global ischemia-induced myocardial damage and coronary endothelial dysfunction. This study aimed to determine whether esaxerenone exerted cardioprotective effects against cardioplegic arrest in Wistar rat hearts. METHODS: Isolated male Wistar rat hearts aerobically perfused via the Langendorff method for 20 min were randomly allocated to the Control (n = 6; perfused for an additional 10 min and subjected to no treatment) or Esax (n = 6; perfused with 0.1 µmol/L esaxerenone in perfusate for 10 min before ischemia) groups. Hearts in both groups were perfused with St. Thomas' Hospital No. 2 solution (STH2) for 2 min and subjected to 28 min of global ischemia. The recovery of left ventricular developed pressure (LVDP) and total troponin T leakage were measured after reperfusion. RESULTS: The final recovery of LVDP (expressed as a percentage of pre-ischemic value) in the Control and Esax groups was 50.8 ± 3.5% and 62.1 ± 5.6%, respectively (p <0.05, Esax vs. Control). The total troponin T leakage in the Control and Esax groups was 138.8 ± 18.5 ng/g heart wt and 74.3 ± 18.6 ng/g heart wt, respectively (p <0.05, Esax vs. Control). CONCLUSION: The administration of esaxerenone before cardioplegic arrest enhanced the cardioprotective effect exerted by STH2.
Assuntos
Modelos Animais de Doenças , Parada Cardíaca Induzida , Preparação de Coração Isolado , Antagonistas de Receptores de Mineralocorticoides , Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Sulfonas , Troponina T , Função Ventricular Esquerda , Pressão Ventricular , Animais , Masculino , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Troponina T/sangue , Fatores de Tempo , Sulfonas/farmacologia , Pressão Ventricular/efeitos dos fármacos , Recuperação de Função Fisiológica , Miocárdio/metabolismo , Miocárdio/patologia , Soluções Cardioplégicas/farmacologia , PirróisRESUMO
BACKGROUND: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. METHODS: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 µmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. RESULTS: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. CONCLUSION: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.
Assuntos
Proteínas Quinases Ativadas por AMP , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Autofagia , Chalconas , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Masculino , Ratos , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Linhagem Celular , Chalconas/farmacologia , Modelos Animais de Doenças , Fibrose , Infarto do Miocárdio/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Two-dimensional ultrasound (2DUS) echocardiography is the main noninvasive method used to evaluate cardiac function in animal models of myocardial infarction (MI). However, 2DUS echocardiography does not capture regional differences in cardiac contractility since it relies on planar images to estimate left ventricular (LV) geometry and global function. Thus, the current study was designed to evaluate the efficacy of a newly developed 4-dimensional ultrasound (4DUS) method in detecting cardiac functional differences between two models of MI, permanent ligation (PL), and ischemia/reperfusion (I/R) in rats. We found that only 4DUS was able to detect LV global functional differences between the two models and that 4DUS-derived surface area strain accurately detected infarcted regions within the myocardium that correlated well with histological infarct size analysis. We also found that 4DUS-derived strain, which includes circumferential, longitudinal, and surface area strain, correlated with the peak positive of the first derivative of left ventricular pressure (+dP/dtmax). In conclusion, 4DUS strain echocardiography effectively assesses myocardial mechanics following experimentally induced ischemia in rats and accurately estimates infarct size as early as 1 day after injury. 4DUS also correlates well with +dP/dtmax, a widely used marker of cardiac contractility.
Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Ratos Sprague-Dawley , Animais , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/patologia , Ratos , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ecocardiografia Quadridimensional/métodos , Contração Miocárdica , Função Ventricular Esquerda , Modelos Animais de DoençasRESUMO
Cardiovascular disease remains the leading cause of death worldwide, with acute myocardial infarction and anticancer drug-induced cardiotoxicity being the significant factors. The most effective treatment for acute myocardial infarction is rapid restoration of coronary blood flow by thrombolytic therapy or percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury (MI/RI) after reperfusion therapy is common in acute myocardial infarction, thus affecting the prognosis of patients with acute myocardial infarction. There is no effective treatment for MI/RI. Anthracyclines such as Doxorubicin (DOX) have limited clinical use due to their cardiotoxicity, and the mechanism of DOX-induced cardiac injury is complex and not yet fully understood. N6-methyladenosine (m6A) plays a crucial role in many biological processes. Emerging evidence suggests that m6A methylation plays a critical regulatory role in MI/RI and DOX-induced cardiotoxicity (DIC), suggesting that m6A may serve as a novel biomarker and therapeutic target for MI/RI and DIC. M6A methylation may mediate the pathophysiological processes of MI/RI and DIC by regulating cellular autophagy, apoptosis, oxidative stress, and inflammatory response. In this paper, we first focus on the relationship between m6A methylation and MI/RI, then further elucidate that m6A methylation may mediate the pathophysiological process of MI/RI through the regulation of cellular autophagy, apoptosis, oxidative stress, and inflammatory response. Finally, briefly outline the roles played by m6A in DIC, which will provide a new methodology and direction for the research and treatment of MI/RI and DIC.
Assuntos
Adenosina , Apoptose , Cardiotoxicidade , Doxorrubicina , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo , Doxorrubicina/efeitos adversos , Animais , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Metilação , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Transdução de Sinais , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Mediadores da Inflamação/metabolismoRESUMO
INTRODUCTION: The comorbidities of ischemic heart disease (IHD) and diabetes mellitus (DM) compromise the protection of the diabetic heart from ischemia/reperfusion (I/R) injury. We hypothesized that manipulation of reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways might protect the diabetic heart, and intervention of these pathways could be a new avenue for potentially protecting the diabetic heart. METHODS: All hearts were subjected to 30-min ischemia and 30-min reperfusion. During reperfusion, hearts were exposed to molecules proven to protect the heart from I/R injury. The hemodynamic data were collected using suitable software. The infarct size, troponin T levels, and protein levels in hearts were evaluated. RESULTS: Both cyclosporine-A and nitric oxide donor (SNAP) infusion at reperfusion protected 4-week diabetic hearts from I/R injury. However, 6-week diabetic hearts were protected only by SNAP, but not cyclosporin-A. These treatments significantly (p < 0.05) improved cardiac hemodynamics and decreased infarct size. CONCLUSIONS: The administration of SNAP to diabetic hearts protected both 4- and 6-week diabetic hearts; however, cyclosporine-A protected only the 4-week diabetic hearts. The eNOS/GLUT-4 pathway executed the SNAP-mediated cardioprotection.
Assuntos
Ciclosporina , Diabetes Mellitus Experimental , Traumatismo por Reperfusão Miocárdica , Miocárdio , Doadores de Óxido Nítrico , Óxido Nítrico , Transdução de Sinais , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Diabetes Mellitus Experimental/complicações , Masculino , Ciclosporina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Fatores de Tempo , Ratos Sprague-Dawley , Troponina T/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/complicações , Transportador de Glucose Tipo 4Assuntos
Soluções Cardioplégicas , Traumatismo por Reperfusão Miocárdica , Animais , Soluções Cardioplégicas/administração & dosagem , Soluções Cardioplégicas/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas , Portadores de Fármacos , Parada Cardíaca Induzida/efeitos adversos , Parada Cardíaca Induzida/métodos , Gases , Humanos , Modelos Animais de Doenças , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Cardiotônicos/farmacologia , Cardiotônicos/administração & dosagemRESUMO
Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.
Assuntos
Gasotransmissores , Traumatismo por Reperfusão Miocárdica , Gases Nobres , Humanos , Gasotransmissores/metabolismo , Gasotransmissores/uso terapêutico , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Gases Nobres/metabolismo , Precondicionamento Isquêmico Miocárdico , Transdução de Sinais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologiaRESUMO
AIMS: ßII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of ßII spectrin in cardiac contractile function and pathological post-myocardial infarction remodelling remain unclear. Here, we investigated whether and how ßII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischaemia/reperfusion (I/R) injury. METHODS AND RESULTS: We observed that the levels of serum ßII spectrin breakdown products (ßII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, ßII spectrin was degraded into ßII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific ßII spectrin knockout mice, we found that deletion of ßII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy, and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific ßII spectrin knockout mice had not developed, deletion of ßII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of ßII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that ßII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, ßII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75-kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability. CONCLUSION: ßII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in ßII spectrin exacerbate cardiac I/R injury.
Assuntos
Modelos Animais de Doenças , Mitocôndrias Cardíacas , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Espectrina , Animais , Humanos , Masculino , Calpaína/metabolismo , Calpaína/genética , Calpaína/deficiência , Proteínas de Transporte , Estudos de Casos e Controles , Respiração Celular , Células Cultivadas , Fibrose , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/enzimologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/enzimologia , Proteólise , Espectrina/metabolismo , Espectrina/genética , Função Ventricular Esquerda , Remodelação VentricularRESUMO
Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.
Assuntos
Modelos Animais de Doenças , Infarto do Miocárdio , Animais , Feminino , Suínos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Função Ventricular Esquerda/fisiologia , Volume Sistólico/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodosRESUMO
The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.
Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca , Malonatos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Animais , Malonatos/farmacologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/etiologia , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Função Ventricular Esquerda/efeitos dos fármacos , Fibrose , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fatores de TempoAssuntos
Hipóxia , Precondicionamento Isquêmico Miocárdico , Transdução de Sinais , Animais , Humanos , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Acetilcolina/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.
Assuntos
Arritmias Cardíacas , Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Animais , Ratos , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Masculino , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Diástole/fisiologia , Cloreto de Sódio na Dieta/efeitos adversos , Frequência Cardíaca/fisiologiaRESUMO
Cardiac arrest (CA) remains a leading cause of death, with suboptimal survival rates despite efforts involving cardiopulmonary resuscitation and advanced life-support technology. Post-resuscitation myocardial dysfunction (PRMD) is an important determinant of patient outcomes. Myocardial ischemia/reperfusion injury underlies this dysfunction. Previous reports have shown that ruthenium red (RR) has a protective effect against cardiac ischemia-reperfusion injury; however, its precise mechanism of action in PRMD remains unclear. This study investigated the effects of RR on PRMD and analyzed its underlying mechanisms. Ventricular fibrillation was induced in rats, which were then subjected to cardiopulmonary resuscitation to establish an experimental CA model. At the onset of return of spontaneous circulation, RR (2.5 mg/kg) was administered intraperitoneally. Our study showed that RR improved myocardial function and reduced the production of oxidative stress markers such as malondialdehyde (MDA), glutathione peroxidase (GSSG), and reactive oxygen species (ROS) production. RR also helped maintain mitochondrial structure and increased ATP and GTP levels. Additionally, RR effectively attenuated myocardial apoptosis. Furthermore, we observed downregulation of proteins closely related to mitophagy, including ubiquitin-specific protease 33 (USP33) and P62, whereas LC3B (microtubule-associated protein light chain 3B) was upregulated. The upregulation of mitophagy may play a critical role in reducing myocardial injury. These results demonstrate that RR may attenuate PRMD by promoting mitophagy through the inhibition of USP33. These effects are likely mediated through diverse mechanisms, including antioxidant activity, apoptosis suppression, and preservation of mitochondrial integrity and energy metabolism. Consequently, RR has emerged as a promising therapeutic approach for addressing post-resuscitation myocardial dysfunction.
Assuntos
Modelos Animais de Doenças , Parada Cardíaca , Mitofagia , Ratos Sprague-Dawley , Rutênio Vermelho , Animais , Mitofagia/efeitos dos fármacos , Parada Cardíaca/complicações , Parada Cardíaca/tratamento farmacológico , Parada Cardíaca/metabolismo , Parada Cardíaca/fisiopatologia , Ratos , Masculino , Rutênio Vermelho/farmacologia , Rutênio Vermelho/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Ubiquitina Tiolesterase/metabolismo , Reanimação Cardiopulmonar , Regulação para Cima/efeitos dos fármacos , Miocárdio/patologia , Miocárdio/metabolismo , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologiaRESUMO
Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial salvage, but the abrupt return of flow sets off a cascade of injurious processes that can lead to further necrosis. This has been termed myocardial ischemia-reperfusion injury and is the subject of this review. The pathologic and molecular bases for myocardial ischemia-reperfusion injury are increasingly understood and include injury from reactive oxygen species, inflammation, calcium overload, endothelial dysfunction, and impaired microvascular flow. A variety of pharmacologic strategies have been developed that have worked well in preclinical models and some have shown promise in the clinical setting. In addition, there are newer mechanical approaches including mechanical unloading of the heart prior to reperfusion that are in current clinical trials.
Assuntos
Traumatismo por Reperfusão Miocárdica , Humanos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/etiologia , Infarto do Miocárdio/fisiopatologia , Reperfusão Miocárdica/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
OBJECTIVES: Flavonoids are polyphenolic compounds found in a wide range of foods, including fruits, vegetables, tea plants, and other natural products. They have been mainly classified as flavanols, flavonols, flavones, isoflavones, flavanones, and flavanonols. In this comprehensive review, we will discuss preclinical pieces of evidence on the potential of flavonoids for the prevention/treatment of myocardial ischemia-reperfusion (IR) injury. KEY FINDINGS: In-vitro and in-vivo studies have shown that flavonoids play an important role in preventing ischemic heart disease (IHD). They possess strong anti-oxidant, anti-inflammatory, anti-bacterial, anti-thrombotic, anti-apoptotic, and anti-carcinogenic activities. In addition, at a molecular level, flavonoids also modulate various pathways like MAPK, NFκB etc. to confer beneficial effects. SUMMARY: The current review of flavonoids in myocardial ischemia-reperfusion injury furnishes updated information that could drive future research. The in-vitro and in-vivo experiments have demonstrated various favourable pharmacological properties of flavonoids. This review provides valuable information to conduct clinical studies, validating the safety aspects of flavonoids in the clinical domain.
Assuntos
Flavonoides , Traumatismo por Reperfusão Miocárdica , Humanos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Flavonoides/farmacologia , Animais , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Apoptose/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêuticoRESUMO
Coronary occlusion (45 min) and reperfusion (120 min) in male Wistar rats in vivo, as well as total ischemia (45 min) of an isolated rat heart followed by reperfusion (30 min) were reproduced. The selective δ2-opioid receptor agonist deltorphin II (0.12 mg/kg and 152 nmol/liter) was administered intravenously 5 min before reperfusion in vivo or added to the perfusion solution at the beginning of reperfusion of the isolated heart. The peripheral opioid receptor antagonist naloxone methiodide and δ2-opioid receptor antagonist naltriben were used in doses of 5 and 0.3 mg/kg, respectively. It was found that the infarct-limiting effect of deltorphin II is associated with the activation of δ2-opioid receptors. We have demonstrated that deltorphin II can improve the recovery of the contractility of the isolated heart after total ischemia.