RESUMEN
Diabetic cardiomyopathy (DCM) is a severe secondary complication of type 2 diabetes mellitus (T2DM) that is diagnosed as a heart disease occurring in the absence of any previous cardiovascular pathology in diabetic patients. Although it is still lacking an exact definition as it combines aspects of both pathologies - T2DM and heart failure, more evidence comes forward that declares DCM as one complex disease that should be treated separately. It is the ambiguous pathological phenotype, symptoms or biomarkers that makes DCM hard to diagnose and screen for its early onset. This re-view provides an updated look on the novel advances in DCM diagnosis and treatment in the experimental and clinical settings. Management of patients with DCM proposes a challenge by itself and we aim to help navigate and advice clinicians with early screening and pharmacotherapy of DCM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Humanos , Cardiomiopatías Diabéticas/terapia , Cardiomiopatías Diabéticas/diagnóstico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Manejo de la Enfermedad , AnimalesRESUMEN
Intermittent hypoxic preconditioning (IHP) is a well-established cardioprotective intervention in models of ischemia/reperfusion injury. Nevertheless, the significance of IHP in different cardiac pathologies remains elusive. In order to investigate the role of IHP and its effects on calcium-dependent signalization in HF, we employed a model of cardiomyopathy induced by doxorubicin (Dox), a widely used drug from the class of cardiotoxic antineoplastics, which was i.p. injected to Wistar rats (4 applications of 4 mg/kg/week). IHP-treated group was exposed to IHP for 2 weeks prior to Dox administration. IHP ameliorated Dox-induced reduction in cardiac output. Western blot analysis revealed increased expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) while the expression of hypoxia inducible factor (HIF)-1-α, which is a crucial regulator of hypoxia-inducible genes, was not changed. Animals administered with Dox had further decreased expression of TRPV1 and TRPV4 (transient receptor potential, vanilloid subtype) ion channels along with suppressed Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation. In summary, IHP-mediated improvement in cardiac output in the model of Dox-induced cardiomyopathy is likely a result of increased SERCA2a expression which could implicate IHP as a potential protective intervention in Dox cardiomyopathy, however, further analysis of observed effects is still required.
Asunto(s)
Cardiomiopatías , Miocitos Cardíacos , Ratas , Animales , Ratas Wistar , Apoptosis , Cardiomiopatías/inducido químicamente , Cardiomiopatías/prevención & control , Cardiomiopatías/metabolismo , Doxorrubicina/toxicidad , Hipoxia/inducido químicamenteRESUMEN
Introduction: Quercetin (Que) is a potent anti-inflammatory and antioxidant flavonoid with cardioprotective potential. However, very little is known about the signaling pathways and gene regulatory proteins Que may interfere with, especially in diabetic cardiomyopathy. Therefore, we aimed to study the potential cardioprotective effects of Que on the cardiac phenotype of type 2 diabetes mellitus (T2DM) accompanied by obesity. Methods: For this experiment, we used Zucker Diabetic Fatty rats (fa/fa) and their age-matched lean controls (fa/+) that were treated with either vehicle or 20 mg/kg/day of Que for 6 weeks. Animals underwent echocardiographic (echo) examination before the first administration of Que and after 6 weeks. Results: After the initial echo examination, the diabetic rats showed increased E/A ratio, a marker of left ventricular (LV) diastolic dysfunction, in comparison to the control group which was selectively reversed by Que. Following the echo analysis, Que reduced LV wall thickness and exhibited an opposite effect on LV luminal area. In support of these results, the total collagen content measured by hydroxyproline assay was decreased in the LVs of diabetic rats treated with Que. The follow-up immunoblot analysis of proteins conveying cardiac remodeling pathways revealed that Que was able to interfere with cardiac pro-hypertrophic signaling. In fact, Que reduced relative protein expression of pro-hypertrophic transcriptional factor MEF2 and its counter-regulator HDAC4 along with pSer246-HDAC4. Furthermore, Que showed potency to decrease GATA4 transcription factor, NFAT3 and calcineurin, as well as upstream extracellular signal-regulated kinase Erk5 which orchestrates several pro-hypertrophic pathways. Discussion: In summary, we showed for the first time that Que ameliorated pro-hypertrophic signaling on the level of epigenetic regulation and targeted specific upstream pathways which provoked inhibition of pro-hypertrophic signals in ZDF rats. Moreover, Que mitigated T2DM and obesity-induced diastolic dysfunction, therefore, might represent an interesting target for future research on novel cardioprotective agents.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Disfunción Ventricular Izquierda , Ratas , Animales , Quercetina/farmacología , Quercetina/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/genética , Epigénesis Genética , Ratas Zucker , Cardiomegalia/genética , Disfunción Ventricular Izquierda/complicaciones , Obesidad/complicacionesRESUMEN
Alternative branches of the classical renin-angiotensin-aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.