title: Suppression of calcium‑sensing receptor ameliorates cardiac hypertrophy through inhibition of autophagy.
abstract: The calcium-sensing receptor (CaSR) releases intracellular calcium ([Ca2+]i) by accumulating inositol phosphate. Changes in [Ca2+]i initiate myocardial hypertrophy. Furthermore, autophagy associated with [Ca2+]i. Autophagy has previously been demonstrated to participate in the hypertrophic process. The current study investigated whether suppression of CaSR affects the hypertrophic response via modulating autophagy. Isoproterenol (ISO) was used to induce cardiac hypertrophy in Wistar rats. Hypertrophic status was determined by echocardiographic assessment, hematoxylin and eosin, and Masson's staining. The protein expression levels of CaSR and autophagy level were observed. Changes of hypertrophy and autophagy indicators were observed following intravenous injection of a CaSR inhibitor. An ISO‑induced cardiomyocyte hypertrophy model was established and used determine the involvement of GdCl3. [Ca2+]i was determined using Fluo‑4/AM dye followed by confocal microscopy. The expression levels of various active proteins were analyzed by western blotting. The size of the heart, expression levels of CaSR and autophagy level were markedly increased in hypertrophic myocardium. In addition, the present study demonstrated that the indicators of hypertrophy and autophagy were effectively suppressed by CaSR inhibitor. Furthermore, similar effects were demonstrated in neonatal rat hypertrophic cardiomyocytes treated with ISO. It was also observed that CaSR regulates the Ca2+/calmodulin‑dependent protein kinase kinase β (CaMKKβ)‑AMP‑activated protein kinase (AMPK)‑mammalian target of rapamycin (mTOR) signaling pathway induced by ISO in cardiomyocytes. Furthermore, the AMPK inhibition significantly reduced the autophagy level following CaSR stimulation (P<0.05). The results of the present demonstrated that inhibition of CaSR may ameliorate cardiac hypertrophy induced by ISO and the effect may be associated with the inhibition of autophagy and suppression of the CaMKKβ‑AMPK‑mTOR signaling pathway.
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Otorhinolaryngology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Qiqihar Medical College, Qiqihar, Heilongjiang 161042, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Sa
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D006332:Cardiomegaly / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D044169:Receptors, Calcium-Sensing; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D007545:Isoproterenol; D002118:Calcium