1. Angiotensin-converting enzyme 2-Angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment
Naim Kittana Fundam Clin Pharmacol . 2018 Feb;32(1):14-25. doi: 10.1111/fcp.12318.
Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hallmark of heart failure (HF). It can be induced by the abnormal elevation of several endogenous factors including angiotensin II (Ang II), which is generated from its precursor angiotensin I (Ang I) by the action of angiotensin-converting enzyme. The inhibition of this enzyme or the blockade of the Ang II receptors demonstrated a high clinical value against the progression of HF. Ang I and Ang II may also be converted into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9), respectively, by the action of angiotensin-converting enzyme 2. Both derivatives demonstrated a promising anticardiac remodeling activity especially against the detrimental effects of Ang II. This manuscript thoroughly reviews the available in vitro and in vivo data on Ang 1-7 and Ang 1-9 in the context of the treatment of HF and discusses the associated molecular mechanisms and the trials to clinically utilize Ang 1-7 mimetics for the treatment of that disease.
2. Angiotensin-(1-9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway
Juan Carlos Roa, María Paz Ocaranza, Pablo Rivera-Mejías, Camila López-Crisosto, Vinicius Maracaja-Coutinho, Gunter Meister, Víctor Aliaga-Tobar, Valentina Parra, Iva Polakovicova, Mario Chiong, Pablo E Morales, Beverly A Rothermel, Lorena García, Christian Pennanen, Alejandro H Corvalán, Cristian Sotomayor-Flores, Sergio Lavandero, César Vásquez-Trincado, Hung Ho-Xuan Cell Death Differ . 2020 Sep;27(9):2586-2604. doi: 10.1038/s41418-020-0522-3.
Angiotensin-(1-9) is a peptide from the noncanonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. In the present study we aimed to elucidate it, basing us initially on previous work from our group and colleagues who proved a relationship between disturbances in mitochondrial morphology and calcium handling, associated with the setting of cardiac hypertrophy. Our first finding was that angiotensin-(1-9) can induce mitochondrial fusion through DRP1 phosphorylation. Secondly, angiotensin-(1-9) blocked mitochondrial fission and intracellular calcium dysregulation in a model of norepinephrine-induced cardiomyocyte hypertrophy, preventing the activation of the calcineurin/NFAT signaling pathway. To further investigate angiotensin-(1-9) anti-hypertrophic mechanism, we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1-9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that PKA activity is necessary for the effects of angiotensin-(1-9) over mitochondrial dynamics, calcium handling and its anti-hypertrophic effects.
3. Angiotensin-(1-7) and angiotensin-(1-9): function in cardiac and vascular remodelling
Christopher M Loughrey, Clare A McKinney, Caroline Fattah, Graeme Milligan, Stuart A Nicklin Clin Sci (Lond) . 2014 Jun;126(12):815-27. doi: 10.1042/CS20130436.
The RAS (renin-angiotensin system) is integral to cardiovascular physiology; however, dysregulation of this system largely contributes to the pathophysiology of CVD (cardiovascular disease). It is well established that AngII (angiotensin II), the main effector of the RAS, engages the AT1R (angiotensin type 1 receptor) and promotes cell growth, proliferation, migration and oxidative stress, all processes which contribute to remodelling of the heart and vasculature, ultimately leading to the development and progression of various CVDs, including heart failure and atherosclerosis. The counter-regulatory axis of the RAS, which is centred on the actions of ACE2 (angiotensin-converting enzyme 2) and the resultant production of Ang-(1-7) [angiotensin-(1-7)] from AngII, antagonizes the actions of AngII via the receptor Mas, thereby providing a protective role in CVD. More recently, another ACE2 metabolite, Ang-(1-9) [angiotensin-(1-9)], has been reported to be a biologically active peptide within the counter-regulatory axis of the RAS. The present review will discuss the role of the counter-regulatory RAS peptides Ang-(1-7) and Ang-(1-9) in the cardiovascular system, with a focus on their effects in remodelling of the heart and vasculature.