Rostamzadeh Farzaneh, Najafipour Hamid, Yeganeh-Hajahmadi Mahboobeh, Esmaeili-Mahani Saeed, Joukar Siyavash, Iranpour Maryam
Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran.
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.
Life Sci. 2017 Dec 15;191:24-33. doi: 10.1016/j.lfs.2017.09.044. Epub 2017 Oct 4.
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.
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.
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.
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.
κ阿片受体（KORs）可改变apelin对磷酸化细胞外信号调节激酶1/2（pERK1/2）的影响。然而，KOR与apelin受体（APJ）之间的相互作用在apelin对肾血管性高血压（2K1C）大鼠心脏收缩力的影响以及对心脏中pERK1/2和蛋白激酶C（PKC）的调节中的作用尚不清楚。
分别用F13A、去甲二氢吗啡酮（nor-BNI）、白屈菜红碱和百日咳毒素（PTX）抑制APJ、KOR、PKC和Gi通路后，测量2K1C大鼠的血流动力学因素、KOR与APJ的异源二聚化、KOR mRNA和蛋白的表达以及左心室中pERK1/2的表达。
40和60μg/kg剂量的apelin可增加心脏收缩力并降低平均动脉压。F13A、nor-BNI和白屈菜红碱降低了这两种剂量下apelin对心脏的影响，PTX则完全阻断了这种影响。高血压增加了KORs的表达以及APJ与KOR的异源二聚化，并降低了左心室中pERK1/2的表达。两种剂量的apelin均降低了（使正常化）异源二聚化，并恢复了pERK1/2的降低。ERK1/2磷酸化的恢复伴随着KOR与APJ异源二聚化的减少。
2K1C高血压增加了KORs的表达以及APJ与KORs的异源二聚化。这种异源二聚化与ERK磷酸化的减少相关，并改变了apelin对心脏正性肌力和舒张性的作用。这些变化可能参与了与血清apelin水平低于正常相关的肾血管性高血压心脏功能障碍的病理生理学过程。apelin诱导的ERK1/2磷酸化和KOR-APJ二聚化的恢复可能使apelin成为治疗此类高血压的一个治疗靶点。
