Alcohol Intake Provoked Cardiomyocyte Apoptosis Via Activating Calcium-Sensing Receptor and Increasing Endoplasmic Reticulum Stress and Cytosolic [Ca2+]i

Article

Author: Liu, Yue ; Zhao, Meng ; Chi, Jinyu ; Zhang, Xin ; Yin, Xinhua ; Liu, Wenxiu

BACKGROUNDCardiomyocyte apoptosis plays an important role in alcoholic cardiac injury. However, the association between calcium-sensing receptor (CaSR) and alcohol-induced cardiomyocyte apoptosis remain unclear. Therefore, we investigated the role and its moleculer mechanism of CaSR in rat cardiomyocyte apoptosis induced by alcohol.METHODSAlcohol-induced cardiomyocyte apoptosis in vivo and in vitro model of rats were applied in this study. The expression of CaSR, endoplasmic reticulum stress markers and apoptosis were tested by immunohistological staining, western blot, TUNEL and flow cytometry, respectively. [Ca²⁺]_i were detected by confocal laser scanning microscopy.RESULTSCompared with the control group, alcohol intake (AI) led to abnormal arrangements of cardiomyocytes and obvious increase of myocardial apoptosis. Moreover, AI also significantly upregulated protein expression of CaSR, GRP94, caspase-12 and CHOP. Alcohol induced apoptosis of cultured cardiomyocytes of rats in a dose-dependent way. Activation of CaSR markedly enhanced cardiomyocyte apoptosis and ERS induced by alcohol, ERS inducer also significantly increased cardiomyocyte apoptosis without activating CaSR. Furthermore, GdCl₃ augmented alcohol-induced increase of [Ca²⁺]_i in cardiomyocytes, which was attenuated by NPS2390 but not 4-PBA pre-treatment.CONCLUSIONSAlcohol could induce cardiomyocyte apoptosis in rats in vivo and in vitro, which was mediated probably via activating CaSR, and then ERS and the increase of the cytosolic [Ca²⁺]_i. This provides a potential target for preventing cardiomyocyte apoptosis and cardiomyopathy induced by alochol.

01 Aug 2021·Microcirculation

Chronic hypoxia promoted pulmonary arterial smooth muscle cells proliferation through upregulated calcium‐sensing receptorcanonical transient receptor potential 1/6 pathway

Article

Author: Peng, Gongyong ; Cao, Weitao ; Huang, Lingmei ; Xu, Juan ; Fu, Zhenli ; Jiang, Yongliang ; Pu, Jinding ; Li, Shaoxing ; Ran, Pixin ; Wen, Xing ; Li, Bing ; Liu, Rongmin ; Hong, Wei

AbstractObjectivesAlthough both calcium‐sensing receptor (CaSR) and canonical transient receptor potential (TRPC) proteins contribute to chronic hypoxia (CH)‐induced pulmonary arterial smooth muscle cells (PASMCs) proliferation, the relationship between CaSR and TRPC in hypoxic PASMCs proliferation remains poorly understood. The goal of this study was to identify that CH promotes PASMCs proliferation through CaSR‐TRPC pathway.MethodsRat PASMCs were isolated and treated with CH. Cell proliferation was assessed by cell counting, CCK‐8 assay, and EdU incorporation. CaSR and TRPC expressions were determined by qPCR and Western blotting. Store‐operated Ca2+ entry (SOCE) was assessed by extracellular Ca2+ restoration.ResultsIn PASMCs, CH enhanced the cell number, cell viability and DNA synthesis, which is accompanied by upregulated expression of CaSR, TRPC1 and TRPC6. Negative CaSR modulators (NPS2143, NPS2390) inhibited, whereas positive modulators (spermine, R568) enhanced, the CH‐induced increases in cell number, cell viability and DNA synthesis in PASMCs. Knockdown of CaSR by siRNA inhibited the CH‐induced upregulation of TRPC1 and TRPC6 and enhancement of SOCE and attenuated the CH‐induced enhancements of cell number, cell viability and DNA synthesis in PASMCs. However, neither siTRPC1 nor siTRPC6 had an effect on the CH‐induced CaSR upregulation, although both significantly attenuated the CH‐induced enhancements of cell number, cell viability and DNA synthesis in PASMCs.ConclusionThese results demonstrate that upregulated CaSR‐TRPC1/6 pathway mediating PASMCs proliferation is an important pathogenic mechanism under hypoxic conditions.

01 Jan 2021·Renal FailureQ4 · MEDICINE

Calcium-sensing receptor promotes calcium oxalate crystal adhesion and renal injury in Wistar rats by promoting ROS production and subsequent regulation of PS ectropion, OPN, KIM-1, and ERK expression

Q4 · MEDICINE

ArticleOA

Author: Li, Xiaoran ; Bao, Junsheng ; Feng, Demei ; Wu, Huang ; Fu, Yuqiang ; Chen, Siyu ; Lu, Jianzhong

OBJECTIVESTo explore the mechanism of calcium-sensing receptors (CaSRs) during the development of nephrolithiasis.MATERIALS AND METHODSWistar rats were treated with ethylene glycol to induce calcium oxalate crystallization, and gadolinium chloride (GdCl₃, an agonist of CaSR) and NPS 2390 (an antagonist of CaSR) were added. Oxidative stress (OS) and calcium oxalate crystals in the kidney were observed. CaSR expression and the expression of extracellular signal-regulated protein kinase (ERK), OPN, and KIM-1 were determined by western blotting. In addition, renal tubular epithelial cells were isolated from the kidney to observe phosphatidylserine (PS) ectropion using flow cytometric analysis. Various biochemical parameters were assessed in serum and urine at the end of the experiment.RESULTSCalcium oxalate increased OS, crystal adhesion, PS ectropion, and the expression of CaSR and ERK, OPN, and KIM-1 in vivo. In addition, lower levels of urine citrate as well as increased serum creatinine and urea levels were observed after treatment with calcium oxalate (p < .05). Compared with calcium oxalate treatment alone, the above deleterious changes were further significantly confirmed by GdCl₃ but were reversed by NPS-2390. However, urine calcium excretion was decreased after ethylene glycol treatment but was significantly reduced by NPS 2390 and increased by GdCl₃ (p < .05).CONCLUSIONSThe results suggest that CaSR might play significant roles in the induction of nephrolithiasis in rats by regulating reactive oxygen species (ROS) and PS ectropion and the composition of urine, OPN, KIM-1, and ERK expression.

100 Deals associated with NPS-2390

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Preclinical	CN	Harbin Medical University	11 Jul 2019
Stroke	Preclinical	US	NPS Pharmaceuticals, Inc.	03 Jun 1999
Epilepsy	Preclinical	US	NPS Pharmaceuticals, Inc.	-

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