Les mécanismes sous-jacents aux effets pathologiques cardiaques de l’angiotensine II dans le remodelage électrique et contractile entre les sexes

Heart failure (HF) is associated with a high mortality and hospitalisations rate causing an important economic burden. The two main causes of mortality in HF are severe ventricular arrhythmias and myocardial stunning. It is now recognized that angiotensin II (ANGII) is one of the main effectors of HF and its deleterious roles are mediated through the activation of the ANGII type 1 (AT1) receptor. Even though it has been shown that ANGII can induce cardiac hypertrophy, its impact on cardiac arrhythmias remains incompletely understood. Therefore, it seems essential to better understand the underlying electrical and contractile mechanisms associated with a chronic ANGII stimulation in order to improve HF therapy. There is a misperception that women are protected against cardiovascular diseases. Nevertheless, a higher number of women die of HF than men. Risk factors also impact differently men and women. The mechanisms underlying these differences are still poorly understood. Furthermore, women frequently receive an inappropriate diagnosis or treatment because of unacknowledged sex differences. This lack of knowledge may result from the fact that women and female animals are too often underrepresented in clinical trials or basic research studies even though they represent 50 % of the population. As a consequence, our knowledge on women pathology is significantly limited. Hence, these observations warrant further investigation to better comprehend sex differences especially in the manifestation and progression of HF. Transgenic mice with a cardiomyocyte specific overexpression of the AT1 receptor (AT1R) have been used to study the electrical, structural and contractile changes occurring before and after the development of hypertrophy. It was first observed in AT1R male mice that ventricular conduction was slowed independently of hypertrophy. This result was due to a reduction in Na+ current density, but not channel expression. Consequently, the involvement of protein kinase C (PKC) in the regulation of the Na+ current by ANGII was studied and results obtained from mouse and human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) suggest that PKCα is responsible for the reduction in Na+ current observed in AT1R male mice and after chronic ANGII exposure. Subsequently, sex differences were also investigated in AT1R mice. We observed that female AT1R mice have a higher mortality rate compared to males suggesting they are more sensitive to AT1R overexpression. Since ventricular electrical remodeling was similarly altered between AT1R mice of both sexes it could not explain the higher mortality rate of AT1R females. Accordingly, cardiac function and Ca2+ dynamics were evaluated next and the data showed that AT1R females develop more severe ventricular hypertrophy and dilation than males. In addition, AT1R females had a small Ca2+ transients, slower Ca2+ reuptake along with a higher Ca2+ spark frequency which could contribute to poor contraction and cardiac arrhythmias through the promotion of delayed after depolarization.  In conclusion, ANGII is implicated in electrical, structural and Ca2+ handling remodeling that promotes poor prognosis associated with HF. Furthermore, these alterations affected female mice more severely highlighting important sex differences in the manifestation of HF.

Keyphrases: hiPSC-CM, Angiotensin II type 1 receptor, Sex differences, Ventricular arrhythmias, Na+ current, Protein kinase Cα, Ca2+ handling, Hypertrophy, Transgenic mouse