RESUMEN
Mitochondria play an important role in both cell survival and cell death. In response to oxidative stress, they undergo opening of non-selective permeability transition pores (PTP) in the inner mitochondrial membrane. Sustained PTP opening triggers mitochondrial swelling due to increased colloidal osmotic pressure in the matrix accompanied by mitochondrial membrane depolarization and ATP hydrolysis. Mitochondrial swelling is the major factor leading to mitochondria-mediated cell death through both apoptosis and necrosis. Hence, precise estimation of the threshold parameters of the transition of reversible swelling to irreversible swelling is important for understanding the mechanisms of PTP-mediated cell death as well as for the development of new therapeutic approaches targeting the mitochondria under pathological conditions. In this study, we designed a simple kinetic model of the Ca2+ -induced mitochondrial swelling that describes the mechanisms of transition from reversible to irreversible swelling in cardiac mitochondria. Values of kinetic parameters calculated using parameter estimation techniques that fit experimental data of mitochondrial swelling with minimum average differences between the experimental data and model parameters. Overall, this study provides a kinetic model verified by data simulation and model fitting that adequately describes the dynamics of mitochondrial swelling.
Asunto(s)
Permeabilidad de la Membrana Celular/genética , Mitocondrias Cardíacas/genética , Dilatación Mitocondrial/genética , Miocardio/metabolismo , Animales , Apoptosis/genética , Calcio/química , Muerte Celular/genética , Supervivencia Celular/genética , Corazón/fisiología , Mitocondrias Cardíacas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial , Membranas Mitocondriales/química , Membranas Mitocondriales/metabolismo , Necrosis/genética , Presión Osmótica , Estrés Oxidativo/genética , Porosidad , RatasRESUMEN
Transition from compensated to decompensated left ventricular hypertrophy (LVH) is accompanied by functional and structural changes. Here, the aim was to evaluate dystrophin expression in murine models and human subjects with LVH by transverse aortic constriction (TAC) and aortic stenosis (AS), respectively. We determined whether doxycycline (Doxy) prevented dystrophin expression and myocardial stiffness in mice. Additionally, ventricular function recovery was evaluated in patients 1 year after surgery. Mice were subjected to TAC and monitored for 3 weeks. A second group received Doxy treatment after TAC. Patients with AS were stratified by normal left ventricular end-diastolic wall stress (LVEDWS) and high LVEDWS, and groups were compared. In mice, LVH decreased inotropism and increased myocardial stiffness associated with a dystrophin breakdown and a decreased mitochondrial O2 uptake (MitoMVO2). These alterations were attenuated by Doxy. Patients with high LVEDWS showed similar results to those observed in mice. A correlation between dystrophin and myocardial stiffness was observed in both mice and humans. Systolic function at 1 year post-surgery was only recovered in the normal-LVEDWS group. In summary, mice and humans present diastolic dysfunction associated with dystrophin degradation. The recovery of ventricular function was observed only in patients with normal LVEDWS and without dystrophin degradation. In mice, Doxy improved MitoMVO2. Based on our results it is concluded that the LVH with high LVEDWS is associated to a degradation of dystrophin and increase of myocardial stiffness. At least in a murine model these alterations were attenuated after the administration of a matrix metalloprotease inhibitor.
Asunto(s)
Distrofina/deficiencia , Hipertrofia Ventricular Izquierda/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocardio/metabolismo , Proteolisis , Animales , Modelos Animales de Enfermedad , Doxiciclina/efectos adversos , Doxiciclina/farmacología , Humanos , Hipertrofia Ventricular Izquierda/inducido químicamente , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Masculino , Ratones , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/patología , Miocardio/patologíaRESUMEN
There is a high prevalence of heart failure (HF) in the general population, but it is more common in black people. We evaluated the association between genomic ancestry and mitochondrial haplogroups (mt-haplogroups) with HF etiology in 503 Brazilian patients. We elicited Mt-haplogroups by analyzing the control region of mitochondrial DNA, and genomic ancestry, by using 48 autosomal insertion-deletion ancestry informative markers. Hypertensive (28.6%, n=144) and ischemic (28.4%, n=143) etiologies of HF were the most prevalent herein. Our results showed that 233 individuals (46.3%) presented African mitochondrial (mt)-haplogroups, and the major contribution in the genomic ancestry analysis was the European ancestry (57.5% (±22.1%)). African mt-haplogroups were positively associated with a diagnosis of hypertensive cardiomyopathy (odds ratio, OR 1.55, confidence interval, CI 95% 1.04-2.44, P=0.04) when compared with European mt-haplogroups. Regarding the genomic ancestry, the African ancestry variant had higher risks (OR 7.84, 95% CI 2.81-21.91, P<0.001), whereas the European ancestry variant had lower risks (OR 0.14, 95% CI 0.04-5.00, P<0.001) for developing the hypertensive etiology. In addition, European ancestry showed an OR of 4.05 (CI 95% 1.53-10.74, P=0.005), whereas African ancestry showed an OR of 0.17 (CI 95% 0.06-0.48, P=0.001) for developing ischemic etiology. In conclusion, this study supports the importance of using ancestry informative markers and mitochondrial DNA to study the genetics of complex diseases in admixed populations to improve the management, treatment and prevention of these illnesses. Therefore, the ancestry informative markers and mt-haplogroups could provide new biomarkers to be associated with HF etiologies and be used as a premise for more specific management.
Asunto(s)
ADN Mitocondrial/genética , Insuficiencia Cardíaca/genética , Mitocondrias Cardíacas/genética , Brasil/epidemiología , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Haplotipos , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Prevalencia , Estudios ProspectivosRESUMEN
One of the most frequent causes of death in developed countries is sudden natural death (SND), which is the most common indication for medico-legal autopsies. Cardiac diseases are frequently detected among SND. Mitochondrial DNA (mtDNA) is easily damaged by reactive oxygen species, and it may cause dysfunction in tissues, leading to early events in cardiovascular disease. A specific mtDNA deletion of 4977 bp is associated to aging, myocardial dysfunction, and bioenergetic deficit. The potential link between mtDNA damage and SND has not been investigated before. Our aim was to evaluate the accumulation of the common mtDNA4977-deletion in cardiac muscle samples from autopsies of SND in adults (n = 14) in comparison to control samples from unnatural deaths (n = 12). Serial dilution-polymerase chain reaction method was performed to estimate the proportion of the total mtDNA harboring the mtDNA4977-deletion. Coefficient variation intra-assay was 8%, and inter-assay was 12%. MtDNA4977-deletion percentage was higher in samples obtained from victims of SND than in those from subjects who died of unnatural causes (p < 0.05). No differences in mtDNA4977-deletion were found between SND victims 39-51 years old, and no correlation was found between these samples and age, r = 0.30, p = 0.29 while it was significant among control samples, r = 0.68, p < 0.05. The association between mtDNA4977 deletion with SND victims might offer a tool to provide additional information to clarify complex SND investigations.