Abstract
The activation of the renin-angiotensin system (RAS) participates in the development of metabolic syndrome (MetS) and in heart failure. PPAR-alpha activation by fenofibrate reverts some of the effects caused by these pathologies. Recently, nonclassical RAS components have been implicated in the pathogenesis of hypertension and myocardial dysfunction; however, their cardiac functions are still controversial. We evaluated if the nonclassical RAS signaling pathways, directed by angiotensin III and angiotensin-(1-7), are involved in the cardioprotective effect of fenofibrate during ischemia in MetS rats. Control (CT) and MetS rats were divided into the following groups: (a) sham, (b) vehicle-treated myocardial infarction (MI-V), and (c) fenofibrate-treated myocardial infarction (MI-F). Angiotensin III and angiotensin IV levels and insulin increased the aminopeptidase (IRAP) expression and decreased the angiotensin-converting enzyme 2 (ACE2) expression in the hearts from MetS rats. Ischemia activated the angiotensin-converting enzyme (ACE)/angiotensin II/angiotensin receptor 1 (AT1R) and angiotensin III/angiotensin IV/angiotensin receptor 4 (AT4R)-IRAP axes. Fenofibrate treatment prevented the damage due to ischemia in MetS rats by favoring the angiotensin-(1-7)/angiotensin receptor 2 (AT2R) axis and inhibiting the angiotensin III/angiotensin IV/AT4R-IRAP signaling pathway. Additionally, fenofibrate downregulated neprilysin expression and increased bradykinin production. These effects of PPAR-alpha activation were accompanied by a reduction in the size of the myocardial infarct and in the activity of serum creatine kinase. Thus, the regulation of the nonclassical axis of RAS forms part of a novel protective effect of fenofibrate in myocardial ischemia.
Highlights
The renin-angiotensin system (RAS) is a complex hormone system that plays a critical role in cardiovascular physiology
Ang IV binds to the angiotensin type 4 receptor (AT4), identified as an insulin-regulated aminopeptidase (IRAP), and it plays a potential role in the regulation of glucose homeostasis and inflammatory processes and in the metabolism of various hormones including vasopressin, oxytocin, and somatostatin [5, 6]
After myocardial infarction (MI), Creatine kinase (CK) activity was significantly higher in metabolic syndrome (MetS) than in CT rats treated with vehicle (Table 1)
Summary
The renin-angiotensin system (RAS) is a complex hormone system that plays a critical role in cardiovascular physiology. The nonclassical RAS, composed mainly by the angiotensinconverting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(17))/Mas receptor (MasR)/angiotensin receptor 2 (AT2R) pathway, improves the cardiac function of hearts subjected to myocardial infarction (MI) and has a beneficial role in insulin resistance, hypertriglyceridemia, fatty liver disease, and obesity [1,2,3,4]. Ang IV binds to the angiotensin type 4 receptor (AT4), identified as an insulin-regulated aminopeptidase (IRAP), and it plays a potential role in the regulation of glucose homeostasis and inflammatory processes and in the metabolism of various hormones including vasopressin, oxytocin, and somatostatin [5, 6]. Ang III and APA are potential therapeutic targets for the treatment of hypertension; the roles of Ang III and Ang IV in cardiac function remain controversial [7,8,9,10]
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