Original ArticleContribution of renin–angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats
Introduction
Hypertension is a major public health problem, affecting approximately one billion people worldwide [1]. Compared with normotensive control subjects, humans with essential hypertension [2], spontaneously hypertensive rats (SHR) [3], and two-kidney–one-clip (2K1C) hypertensive rats [4] exhibit aortic remodeling including aortic hypertrophy and collagen accumulation, and impaired endothelium-dependent vasorelaxation, which are now considered as key factors responsible for the progression of hypertension and its increased morbidity and mortality [5], [6].
The renin–angiotensin system (RAS) plays an important role in the control of cardiovascular homeostasis, and it is one of the most important pathogenic factors in hypertension [7], [8]. Angiotensin II (AngII), an octapeptide hormone, is the central active component of the RAS. The main known actions of AngII are mediated by AT1 receptors (AT1R), including cell proliferation, apoptosis, cell migration, extracellular matrix deposition, and inflammation [9]. In addition to classical pathway of RAS [angiotensin-converting enzyme (ACE), AngII, and AT1R], newly discovered RAS components such as ACE2, Ang-(1–7), and receptor Mas have been shown to play an important role in blood pressure (BP) regulation and target organ damage, by counteracting the classical pathway [10].
Exercise training, as a nonpharmacological antihypertensive therapy, prevented aortic remodeling and preserved endothelial function in healthy and hypertensive humans and animal models [11], [12], [13]. Izawa et al. [14] reported that acute or chronic exercise altered AngII-induced contraction of rat aorta. Exercise training in obese Zucker rats [15] or myocardial infarct rats [16] suppressed cardiac ACE activity and AngII formation. Fernandes et al. [17] reported that exercise training-induced left ventricular hypertrophy involved reduced ACE activity and AngII, and increased ACE2 and Ang-(1–7). In the aortas of SHR, exercise training improved the vasodilator effect of Ang-(1–7) and increased Mas receptors expression [18]. However, the effect of exercise training on components of RAS in the aortas of SHR has not been fully elucidated.
MicroRNAs are endogenous, small, and noncoding RNAs, which are targeted to specific genes and function as negative regulators of gene expression by inhibiting translation or promoting degradation of target messenger RNAs (mRNAs). Recent studies have highlighted the fundamental importance of miRNA in vascular injury and remodeling [19], [20]. Several miRNAs have been reported to be associated with regulation of genes expression of RAS components [21], [22], [23], [24]. This work was designed to systematically examine the impact of exercise training on components of RAS and explore the underlying mechanism of microRNA-mediated gene regulation in the aortas of SHR.
Section snippets
Animals
Ten-week-old male SHR and age-matched normotensive Wistar–Kyoto rats (WKYs) were provided by Vital River Laboratory Animal Technology Company (Beijing, China). All animals were entrained to controlled temperature (24±1°C), 12-h light and 12-h dark cycles (light, 0800–2000 h; darkness, 2000–0800 h), and free access to food and tap water.
Ethical approval
All the animals used in this work received humane care in compliance with institutional animal care guidelines and were approved by the Local Institutional
Hemodynamic parameters and ventricular morphology
As shown in Table 1, SBP and DBP in SHR were higher, when compared to WKY. Exercise training in SHR led to a reduction of SBP and DBP. HR was similar among four groups.
Body weight was similar between WKY and SHR rats. Exercise training lowered body weight in both WKY and SHR rats.
After the period of 12 weeks of exercise, the activity of CS in the soleus muscle was significantly higher in SHR as well as in WKY rats compared with their sedentary control groups, indicating the efficacy of the
Discussion
Exercise training attenuated aortic remodeling including smooth muscular cell hyperplasia and collagen deposition and preserved endothelial function in SHR, which was consistent with previous studies [11], [28]. Exercise training led to a reduction in BP, indicating that the beneficial effect of exercise training on aortic remodeling and endothelial function in SHR might be dependent on BP.
In this work, exercise training in SHR reduced circulating AngII levels and aortic AngII levels
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Funding: No funding.
Conflicts of interest disclosure: The authors declare that they have no conflict of interest.
Author contributions: (1) Conception and design of the experiments: Qi Gu and Bing Wang; (2) collection, analysis, and interpretation of data: Qi Gu, Xiao-Feng Zhang, Yan-Ping Ma, Jian-Dong Liu, and Xiao-Ze Wang; (3) drafting of the article: Qi Gu and Bing Wang.