ER stress improvement by aerobic training or enalapril differently ameliorates pathological cardiac remodeling in obese mice.

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.

Crosstalk between the renin-angiotensin system and the endoplasmic reticulum stress in the cardiovascular system: Lessons learned so far.

The renin-angiotensin (Ang) system (RAS) is a complex hormonal system present locally in several tissues such as cardiovascular organs. RAS deregulation through overactivation of the classical arm [Ang-converting enzyme (ACE)/Ang-II/Ang type 1 receptor (AT1R)] has been linked to the development of cardiovascular diseases and activation of endoplasmic reticulum (ER) stress pathways. The ER stress is a condition that, if unresolved, might lead to heart failure, atherosclerosis, hypertension, and endothelial dysfunction. Accumulated evidence has shown that the RAS modulates the UPR activation. Several studies reported increased ER stress markers in response to Ang-II treatment, in both in vivo and in vitro models. Evidence has also pointed that targeting the RAS classical arm through RAS blockers, gene silencing or genetic models leads to lower levels of ER stress markers. Few studies demonstrated protective effects of the counter-regulatory arm (ACE-2/Ang-(1-7)/Mas receptor) over ER stress. However, the crosstalk mechanisms between the arms of the RAS and ER stress remain unclear. In this review, we sought to explore the classical arm of the RAS as a key mechanism in UPR activation and to suggest a possible protective role of the counter-regulatory arm in mitigating ER stress.