Farzaneh Rostamzadeh1, Hamid Najafipour2, Mahboobeh Yeganeh-Hajahmadi3, Saeed Esmaeili-Mahani4, Siyavash Joukar5, Maryam Iranpour6. 1. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran. 2. Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran. Electronic address: najafipourh@kmu.ac.ir. 3. Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran. 4. Department of Biology, Shahid Bahonar University of Kerman, Kerman, Iran. 5. Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran. 6. Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran.
Abstract
AIMS: Kappa Opioid receptors (KORs) change the impact of apelin on the phosphorylated ERK1/2 (pERK1/2). However, the role of interaction between KOR and apelin receptors (APJ) on the cardiac contractility effects of apelin and in regulation of pERK1/2 and PKC in the heart of renovascular hypertensive (2K1C) rats is unknown. MAIN METHODS: Hemodynamic factors, the heterodimerization of KOR and APJ, the expression of KOR mRNA and protein and pERK1/2 in the left ventricle of 2K1C rats were measured following APJ, KOR, PKC and Gi path inhibition by F13A, nor-BNI, chelerythrine and PTX respectively. KEY FINDINGS: Apelin in 40 and 60μg/kg doses increased cardiac contractility, and reduced mean arterial pressure. The cardiac impacts in both doses were reduced by F13A, nor-BNI and chelerytrine and blocked by PTX. Hypertension increased the expression of KORs and heterodimerization of APJ and KOR, and reduced pERK1/2 in the left ventricle. Apelin, in both doses reduced (normalized) heterodimerization and recovered the reduction in pERK1/2. The recovery of ERK1/2 phosphorylation was accompanied by reduction of KOR and APJ heterodimerization. SIGNIFICANCE: 2K1C hypertension increased the expression of KORs and heterodimerization of APJ and KORs. The heterodimerization was associated by reduction of ERK phosphorylation and altered the cardiac inotropic and lusitropic effects of apelin. These changes may participate in pathophysiology of cardiac dysfunction in renovascular hypertension that is associated with subnormal level of serum apelin. Apelin- induced recovery of ERK1/2 phosphorylation and KOR-APJ dimerization may nominate apelin as a therapeutic goal in treatment of this kind of hypertension.
AIMS: Kappa Opioid receptors (KORs) change the impact of apelin on the phosphorylated ERK1/2 (pERK1/2). However, the role of interaction between KOR and apelin receptors (APJ) on the cardiac contractility effects of apelin and in regulation of pERK1/2 and PKC in the heart of renovascular hypertensive (2K1C) rats is unknown. MAIN METHODS: Hemodynamic factors, the heterodimerization of KOR and APJ, the expression of KOR mRNA and protein and pERK1/2 in the left ventricle of 2K1C rats were measured following APJ, KOR, PKC and Gi path inhibition by F13A, nor-BNI, chelerythrine and PTX respectively. KEY FINDINGS: Apelin in 40 and 60μg/kg doses increased cardiac contractility, and reduced mean arterial pressure. The cardiac impacts in both doses were reduced by F13A, nor-BNI and chelerytrine and blocked by PTX. Hypertension increased the expression of KORs and heterodimerization of APJ and KOR, and reduced pERK1/2 in the left ventricle. Apelin, in both doses reduced (normalized) heterodimerization and recovered the reduction in pERK1/2. The recovery of ERK1/2 phosphorylation was accompanied by reduction of KOR and APJ heterodimerization. SIGNIFICANCE: 2K1C hypertension increased the expression of KORs and heterodimerization of APJ and KORs. The heterodimerization was associated by reduction of ERK phosphorylation and altered the cardiac inotropic and lusitropic effects of apelin. These changes may participate in pathophysiology of cardiac dysfunction in renovascular hypertension that is associated with subnormal level of serum apelin. Apelin- induced recovery of ERK1/2 phosphorylation and KOR-APJ dimerization may nominate apelin as a therapeutic goal in treatment of this kind of hypertension.
Authors: Lukas Dehe; Mohammed Shaqura; Michael Nordine; Helmut Habazettl; Petra von Kwiatkowski; Helena Schluchter; Mehdi Shakibaei; Shaaban A Mousa; Michael Schäfer; Sascha Treskatsch Journal: Cardiovasc Drugs Ther Date: 2021-01-23 Impact factor: 3.727
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