Myocardial infarction (MI) is a progressive disorder of myocardial necrosis due to an acute disturbance of the coronary blood supply [1]. It may lead to a number of life-threatening mechanical or arrhythmic complications. There is a rapid progression in the number of people suffering from MI [2]. In the USA, about 25% of deaths are associated with heart diseases each year, and one American dies every 60 s due to MI [3]. It has been estimated that around 17.9 million people worldwide died from cardiovascular diseases in 2016, representing 31% of all global deaths that year [4]. In Egypt, CVD has been a principal cause of untimely death since the 1990s and, according to the latest WHO data published in 2017, CVDs deaths in Egypt reached 46.2% of total deaths [5]. There is an urgent need to develop cardioprotective agents able to decrease the incidence of myocardial infarction and its accompanied CVD complications following myocardial ischemia.

Many cell death processes are involved in myocardial cell death including necrosis, apoptosis and autophagy [6]. A central constituent of the renin-angiotensin-aldosterone system (RAAS), which controls a variety of physiological processes, is angiotensin converting enzyme 2 (ACE2). It initiates the cleavage of angiotensin II (Ang II) to angiotensin 1-7 (Ang.1-7). Deficiency of ACE2 and increased Ang II upregulates hypoxia-induced genes and impairs cardiac contractility, suggesting a link with myocardial ischemia and necrosis [7].

MicroRNAs (miRNAs) are small noncoding RNAs that obstruct translation or stimulate degradation of mRNA [8] and thus control patterns of gene expression [9]. MiRNAs have a crucial role in the pathogenesis of many cardiovascular diseases, like heart failure, myocardial infarction and fibrosis [10]. Numerous miRNAs have been shown to modulate important processes that participate in the pathophysiology of acute myocardial infarction [11]. MiRNAs can either initiate or impede cardiomyocyte cell death [12]. MiRNA-122 (miR-122) is considered as a candidate novel biomarker in cardiovascular injury [13]. Interestingly, miR-122 has been reported to regulate ACE2 level through targeting Sirt-6, which is considered an ACE2 activator and plays a crucial role in the control of cardiovascular necrosis and dysfunction. Expression of miR-122 is related to the severity of cardiovascular diseases including MI, heart failure and atherosclerosis [14]. MiR-122 could control the apoptosis-autophagy balance of cardiac fibroblasts through targeting the SIRT6-ACE2 pathway and inhibiting Ang II [15].

Adenosine monophosphate-activated protein kinase (AMPK) is an AMP-dependent protein kinase that is a crucial regulator of cellular metabolism and a vital regulator of necrosis inhibition. It plays an essential role in the pathogenesis of many diseases including cancer, diabetes as well as cardiovascular diseases [16]. AMPK activation in heart tissue is an important adaptive response to cardiomyocyte stress that takes place in myocardial ischemia [17]. During ischemia-reperfusion, the decreased level of AMPK was demonstrated to induce myocardial necrosis and contractile dysfunction. Therefore, increasing myocardial SIRT-6 and AMPK levels can represent a potential cardioprotective approach for the prevention of myocardial infarction [18].

Xanthenone is a newly discovered activator of the ACE2/Ang 1–7 axis. It can have a promising modulatory effect on a number of inflammatory and vascular diseases [19]. Xanthenone was reported to have an effect on cerebral ischemia/reperfusion injury through the exertion of vasodilatory, antioxidant, and anti-inflammatory effects [20]. Xanthenone is suggested to inhibit cardiac fibrosis and improve cardiac function via activation of ACE2 and suppression of its substrate Ang II [21]. Upon activation of ACE2, Ang. 1–7 will be markedly increased with a promising cardiovascular protective effect [19,22]. Hence, the current study aims to investigate the cardioprotective effects of xanthenone on myocardial infarction induced experimentally in rats by targeting the miR-122/Sirt-6/ACE2 axis.