Role of angiotensin II in the development of subcellular remodeling in heart failure

Abstract

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dys-function during the progression of heart failure.

Role of Oxidative Stress in Cardiac Dysfunction and Subcellular Defects Due to Ischemia-Reperfusion Injury

“…Extensive research over the past four decades has shown that two major mechanisms, namely the development of oxidative stress and the occurrence of intracellular Ca 2+ -overload, as well as myocardial inflammation and alterations in cardiac metabolism, are considered to explain I/R-induced injury to the heart [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. It should also be mentioned that I/R injury not only affects cardiomyocytes and subcellular organelles but is also known to produce dramatic changes in non-cardiomyocyte structures such as vascular smooth muscle, microvasculature, endothelium, fibroblasts, macrophages, mast cells, adrenergic nerve endings, and endogenous renin-angiotensin system, which are present in the myocardial interstitium [ 5 , 9 , 16 , 17 , 18 ]. Furthermore, I/R-induced injury under in vivo conditions is also associated with the activation of neutrophils, leukocytes, platelets, as well as some systemic and central neuro-endocrine systems [ 7 , 10 , 15 , 19 , 20 , 21 ].…”

Shenkang injection improves chronic kidney disease by inhibiting multiple renin-angiotensin system genes by blocking the Wnt/β-catenin signalling pathway

“…In addition, several publications revealed that rhein improves renal fibrosis and is associated with the nuclear factor kappa B and Twist1 pathways ( Chen et al, 2022 ; Song et al, 2022 ). Many studies have demonstrated that RAS activation is closely associated with various diseases ( Bakhle, 2020 ; Bhullar et al, 2021 ; Lizaraso-Soto et al, 2021 ; Mikusic et al, 2021 ; Walther et al, 2021 ). The presence of a local or tissue-based RAS has been well documented and is considered to be a pivotal player in the pathogenesis of CKD and its complications ( Yang and Xu, 2017 ).…”

Angiotensin II-Induced Signal Transduction Mechanisms for Cardiac Hypertrophy

“…Such effects are also evident upon the activation of both circulating and cardiac RAS and are considered to be elicited by Ang II; however, these actions are independent of each other [ 1 , 5 , 6 , 8 , 17 , 56 ]. While the activation of RAS for a short period has been shown to produce adaptive cardiac hypertrophy for maintaining cardiovascular function, prolonged activation of RAS or exposure of the heart to Ang II for a prolonged period is known to result in maladaptive cardiac hypertrophy, a well-known risk factor for heart failure [ 3 , 4 , 16 , 20 , 26 , 57 ]. It should be noted that besides Ang II, different other biologically active peptides such as Ang-(2-8) (Ang III), Ang-(3-8) (Ang IV) and Ang-(1-7) have been shown to exert dramatic effects on the cardiovascular system [ 9 , 27 ].…”

“…In cardiomyocytes and cardiac fibroblasts, Ang II activated Rac1 (increasing expression of RAC1-GTP), as well as NOX2 and NOX4 involvement in cardiac hypertrophy and fibrosis has been indicated [ 174 , 177 ]. The antioxidants therapies are considered to have an advantage for the treatment of cardiac hypertrophy over ACE inhibitors or AT 1 R blockers [ 17 , 27 , 57 , 61 , 174 , 178 ]. Furthermore, it is suggested that extensive effort should be made to develop appropriate activators of AT 2 R and Mas receptors for preventing or reversing the Ang II- induced pathological cardiac hypertrophy [ 133 , 134 , 143 , 149 ].…”