Abstract
Mitochondrial biosynthesis regulated by the PGC-1α-NRF1-TFAM pathway is considered a novel potential therapeutic target to treat heart failure (HF). Perindopril (PER) is an angiotensin-converting enzyme inhibitor that has proven efficacy in the prevention of HF; however, its mechanism is not well established. In this study, to investigate the mechanisms of PER in cardiac protection, a rat model of cardiomyopathy was established by continuous isoproterenol (ISO) stimulation. Changes in the body weight, heart weight index, echocardiography, histological staining, mitochondrial microstructure, and biochemical indicators were examined. Our results demonstrate that PER reduced myocardial remodeling, inhibited deterioration of cardiac function, and delayed HF onset in rats with ISO-induced cardiomyopathy. PER markedly reduced reactive oxygen species (ROS) production, increased the levels of antioxidant enzymes, inhibited mitochondrial structural destruction and increases the number of mitochondria, improved the function of the mitochondrial respiratory chain, and promoted ATP production in myocardial tissues. In addition, PER inhibited cytochrome C release in mitochondria and caspase-3 activation in the cytosol, thereby reducing the apoptosis of myocardial cells. Notably, PER remarkably up-regulated the mRNA and protein expression levels of Sirtuin 3 (SIRT3), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM) in myocardial cells. Collectively, our results suggest that PER induces mitochondrial biosynthesis-mediated enhancement of SIRT3 and PGC-1α expression, thereby improving the cardiac function in rats with ISO-induced cardiomyopathy.
Highlights
Congestive heart failure (HF) is a common progressive disease, and expanding efforts are being made to develop novel treatments to intervene with its progression and prevent its occurrence (Povsic, 2017)
Evaluation of the serum biochemical index levels suggests that ISO induced B-Type Natriuretic Peptide (BNP) and Angiotensin II (AngII); PER intervention restrained the secretion of these proteins, which suggests that PER mitigates the activation of the neuroendocrine system (Figures 1C, D)
We investigated the mechanism of PER in the ISO-induced myocardial damage rat model
Summary
Congestive heart failure (HF) is a common progressive disease, and expanding efforts are being made to develop novel treatments to intervene with its progression and prevent its occurrence (Povsic, 2017). During HF development, mitochondrial dysfunction in cardiomyocytes is evidenced by decreased cytochrome oxidase activity; and insufficient oxidation of nicotinamide adenine dinucleotide (NADH) can induce the production of reactive oxygen species (ROS) (Bond et al, 2019). Reduced PGC-1a expression is observed in various HF models and is accompanied by oxidative stress (OS) and mitochondrial dysfunction (Piquereau et al, 2017; Waldman et al, 2018). Evidence (Singh et al, 2018; Waldman et al, 2018) suggests that regulation of diabetic cardiomyopathy in a mouse model by either caloric restriction or administration of epoxyeicosatrienoic acid-agonist involves the induction of PGC-1a. Mitochondrial biosynthesis regulated by the PGC-1aNRF1-TFAM pathway has been suggested as the primary mechanism of Carvedilol, a nonselective b-adrenoceptor antagonist that has proven clinical efficacy (Yao et al, 2016). Ample evidence supports the therapeutic potential of drugs that target the PGC-1a pathway
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