Experimental and clinical evidences suggest that apelin and its receptor APJ are involved in the pathogenesis of cardiovascular complications. However, the role of apelin/APJ in hypertension is not sufficiently understood. Because chronic kidney diseases lead to hypertension and cardiac failure, we investigated the changes in apelin receptor gene expression in the myocardium and aorta of rat models of kidney disease hypertension. Two-kidney, one-clip (2K1C) hypertension was produced by placing a clip around the renal artery. Four and 16 weeks later, blood pressure, left ventricular end-diastolic pressure (LVEDP), serum apelin, and angiotensin II were measured. The messenger RNA (mRNA) and protein of APJ were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Chronic hypertensive rats had approximately 10 times higher LVEDP (P < 0.001). 2K1C decreased serum apelin from 220 ± 11 to 170 ± 10 pg/mL in 16 weeks (P < 0.05). The mRNA expression of APJ significantly decreased in the heart and aorta at 4 weeks. At 16 weeks, the reduction was not significant in the heart but was significant in the aorta. At 4 weeks, the expression of the APJ protein significantly decreased in the heart but not in the aorta. At 16 weeks, APJ protein was significantly decreased only in the aorta. Reduction of serum apelin and downregulation of apelin receptors in both the heart and aorta may play a role in the pathophysiology of hypertension and cardiac failure in 2K1C hypertensive rats.

Exercise training (Ex) has beneficial effects on cardiovascular diseases by increasing Klotho and SIRT1. This study aimed to investigate whether the beneficial impact of Ex on myocardial infarction (MI) is mediated through Klotho and SIRT1. Fifty-six Wistar rats were divided into 4 main groups of Sham, MI, Ex, and MI + Ex. MI was induced by the closure of the left anterior descending. Animals were trained by endurance exercise for 4 weeks. In the end, hemodynamic and heart contractility indices were assessed. The levels of Klotho and SIRT1 in the serum and heart were measured by enzyme-linked immunosorbent assay and Western blot, respectively. The ADAM17 level in the heart and kidneys was assessed by enzyme-linked immunosorbent assay. The infarct size and fibrosis area were assessed by triphenyltetrazolium chloride and Masson trichrome staining, respectively. Ex recovered the reduction of dp/dt max and dp/dt min and decreased myocardial infarct size and fibrotic area in the MI group. Ex normalized the increase in heart rate, systolic blood pressure, left ventricular systolic pressure, and left ventricular end diastolic pressure in the MI group. Ex also normalized the reduction of the levels of Klotho and SIRT1 in serum and heart in the MI group. The changes of Klotho and SIRT1 in serum were positively correlated. Ex also restored ADAM17 levels in the MI group. Ex improved cardiac function in the MI group and is associated with reduction of the infarct size and normalization of Klotho and SIRT1 levels. Regarding unidirectional changes in Klotho and SIRT1, these proteins may play a role in beneficial effects of Ex on MI recovery.

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Apelin receptors (APJ) cross-talk with other G-protein-coupled receptors. However, the role of APJ interaction with opioid receptors (OPR) on the cardiovascular effects of apelin in hypertension is not clear. Renovascular hypertension was induced by placing a Plexiglas clip on the left kidney of rats. After 16 weeks, F13A (an APJ antagonist), naloxone (a general OPR inhibitor), and nor-binaltorphimine dihydrochloride (nor-BNI; a selective inhibitor of KOR) were given prior to injections of apelin at doses of 40 and 60 μg/kg. The arterial systolic/diastolic blood pressure and left ventricular contractility responses were then evaluated. The arterial systolic/diastolic blood pressure in sham and 2K1C rats was 110/71 mm Hg and 171/124 mm Hg, respectively. The hypotensive effects of apelin at both doses were inhibited by F13A and naloxone. Nor-BNI completely inhibited the effects of apelin 40 on arterial pressure, and decreased the effects of 60 μg/kg. KOR inhibition also prevented the compensation for the decrease in the left ventricle +dp/dt max and -dp/dt max caused by apelin 60. The simultaneous inhibition of OPR and APJ reduced arterial pressure and increased cardiac contractility. Findings showed that the OPR, particularly KOR, mediate the inotropic, lusitropic, and depressor effects of apelin. The interaction of the OPR and APJ augments the inotropic and vasodepressor effects of apelin. This interaction may have potential clinical applications in cardiac failure since opioids are currently used in the treatment of myocardial infarction and stroke, and apelin has been introduced as a potential therapeutic agent in cardiovascular complications.