Counter- regulatory renin–angiotensin system in cardiovascular disease

The renin–angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II — initially thought to be biologically inactive — have key roles in cardiovascular physiology and pathophysiology. This non- canonical axis of the renin–angiotensin system consists of angiotensin 1–7 , angiotensin 1–9, angiotensin- converting enzyme 2, the type 2 angiotensin II receptor (AT2R), the proto- oncogene Mas receptor and the Mas- related G protein- coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin– angiotensin system. This counter- regulatory renin–angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review , we provide the latest insights into the complexity and interplay of the components of the non- canonical renin–angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) FONDAP 15130011 FONDECYT 1161739 FONDECYT 11181000 FONDECYT 1140713 Puente Pontificia Universidad Catolica de Chile P1705/2017 Bayer AG (Program Grants4Targets) 2017-08-2260 National Council for Scientific and Technological Development (CNPq) 310515/2015-

Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury

Cardiomyocyte loss is the main cause of myocardial dysfunction following an ischemia-reperfusion (IR) injury. Mitochondrial dysfunction and altered mitochondrial network dynamics play central roles in cardiomyocyte death. Proteasome inhibition is cardioprotective in the setting of IR; however, the mechanisms underlying this protection are not well-understood. Several proteins that regulate mitochondrial dynamics and energy metabolism, including Mitofusin-2 (Mfn2), are degraded by the proteasome. The aim of this study was to evaluate whether proteasome inhibition can protect cardiomyocytes from IR damage by maintaining Mfn2 levels and preserving mitochondrial network integrity. Using ex vivo Langendorff-perfused rat hearts and in vitro neonatal rat ventricular myocytes, we showed that the proteasome inhibitor MG132 reduced IR-induced cardiomyocyte death. Moreover, MG132 preserved mitochondrial mass, prevented mitochondrial network fragmentation, and abolished IR-induced reductions in Mfn2 levels in heart tissue and cultured cardiomyocytes. Interestingly, Mfn2 overexpression also prevented cardiomyocyte death. This effect was apparently specific to Mfn2, as overexpression of Miro1, another protein implicated in mitochondrial dynamics, did not confer the same protection. Our results suggest that proteasome inhibition protects cardiomyocytes from IR damage. This effect could be partly mediated by preservation of Mfn2 and therefore mitochondrial integrity.Comisión Nacional de Investigación Científica y Tecnológica (CONICYT, Chile), Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT): 1130407, 1180613, 11170962, 1160704, 1200490, 11181000, 3190546, 3160549. Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), CONICYT FONDAP