Abstract
Inhibition of angiotensin II type 1 receptor (AT1R) is an important therapy in the management of hypertension, particularly in the immediate post-myocardial infarction period. Yet, the role of AT1R in the acute onset of myocardial ischemia and reperfusion injury still remains controversial. Thus, the present study determined the effects of chronic losartan treatment on heart ischemia and reperfusion injury in rats. Losartan (10 mg/kg/day) was administered to six-month-old male rats via an osmotic pump for 14 days and hearts were then isolated and were subjected to ischemia and reperfusion injury in a Langendorff preparation. Losartan significantly decreased mean arterial blood pressure. However, heart weight, left ventricle to body weight ratio and baseline cardiac function were not significantly altered by the losartan treatment. Of interest, chronic in vivo losartan treatment significantly increased ischemia-induced myocardial injury and decreased post-ischemic recovery of left ventricular function. This was associated with significant increases in AT1R and PKCδ expression in the left ventricle. In contrast, AT2R and PKCε were not altered. Furthermore, losartan treatment significantly increased microRNA (miR)-1, -15b, -92a, -133a, -133b, -210, and -499 expression but decreased miR-21 in the left ventricle. Of importance, addition of losartan to isolated heart preparations blocked the effect of increased ischemic-injury induced by in vivo chronic losartan treatment. The results demonstrate that chronic losartan treatment up-regulates AT1R/PKCδ and alters miR expression patterns in the heart, leading to increased cardiac vulnerability to ischemia and reperfusion injury.
Highlights
Heart disease is the leading cause of morbidity and mortality in the United States
Because protein kinase C delta (PKCδ) and protein kinase C epsilon (PKCε) play pivotal roles in the regulation of myocardial ischemic injury and the mechanisms for increased heart susceptibility to ischemia and reperfusion (IR) injury involve the up-regulation of PKCδ and down-regulation of PKCε expression in the heart as demonstrated in previous studies, [17,18,19] we investigated the effects of angiotensin II type 1 receptor (AT1R) blockade on PKCδ and PKCε expression in the left1 ventricle
There were no significant differences in left ventricle developed pressure (LVDP), heart rate (HR), dP/dtmax and dP/dtmin at the baseline between the two groups (Table 1)
Summary
Heart disease is the leading cause of morbidity and mortality in the United States. In addition to other risk factors, clinical and animal studies have shown an association between angiotensin II receptor (ATR) expression on cardiomyocytes and increased risk of ischemic heart diseasePLOS ONE | DOI:10.1371/journal.pone.0132712 July 13, 2015Losartan and Acute Ischemic Injury of the Heart and reduced cardiac recovery after ischemic injury [1,2,3,4,5]. In addition to other risk factors, clinical and animal studies have shown an association between angiotensin II receptor (ATR) expression on cardiomyocytes and increased risk of ischemic heart disease. The heart may experience prolonged ischemia under a variety of conditions, including cardiomyopathy, endothelial dysfunction and coronary arterial disease, valvular dysfunction and hypotension. Animal studies suggest a link between pre-conditioning the heart with angiotensin II type 1 receptor (AT1R) blockers and cardiac protection in ischemia and reperfusion (IR) injury [6,7,8]. AT1R is predominately found in the adult heart and its expression is up-regulated after IR injury [1]. AT1R plays an important role in the regulation of blood pressure, fluid, electrolyte balance, and is involved in pathological conditions such as cardiac remodeling and inflammation [5]. One study indicates AT2R is a direct antagonist by binding to AT1R forming heterodimerization [9]
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