title: Inhibition of the mevalonate pathway ameliorates anoxia-induced down-regulation of FKBP12.6 and intracellular calcium handling dysfunction in H9c2 cells.
abstract: Statins have beneficial pleiotropic effects beyond lipid lowering on the cardiovascular system. These cardio-protective effects are mediated through inhibition of the intracellular mevalonate pathway, by decreasing isoprenoid intermediate synthesis and the subsequent post-translational modification of small GTPases, such as Ras, Rho, and Rac. Impaired intracellular calcium handling is considered an important pathophysiologic mechanism responsible for cardiac dysfunction. Our study aimed at investigating the influence of mevalonate pathway, including its downstream small GTPases (Ras, RhoA, and Rac1) on anoxia-mediated alterations of calcium handling in H9c2 cardiomyocytes. Cultured H9c2 cardiomyocytes were exposed to acute anoxia after pretreatment with different drugs that specifically antagonize five key components in the mevalonate pathway, including 3-hydroxy-3-methylglutaryl-CoA reductase, farnesyl pyrophosphate synthase, Rho-kinase, Rac1 and Ras farnesyltransferase. Thereafter, we evaluated the effects of the mevalonate pathway on anoxia-induced cell death, expression of the sarcoplasmic reticulum calcium release channel (ryanodine receptor 2) and its regulator FK506-binding protein 12.6, as well as functional calcium release from intracellular calcium stores. Our experiments confirmed the role of prenylated proteins in regulating cardiomyocyte dysfunction, especially via RhoA- and Ras-related signaling pathways. Furthermore, our data demonstrated that inhibition of the mevalonate pathway could ameliorate anoxia-mediated calcium handling dysfunction with the up-regulated expression of FK506-binding protein 12.6 and consequently provided evidence for FK506-binding protein 12.6 as a "stabilizer" of ryanodine receptor 2.
authors: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: christineyy2002@163.com.
authors: Ying
authors: Y
authors: Yang
authors: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Xue
authors: X
authors: Lu
authors: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Xiqing
authors: X
authors: Rong
authors: Department of Cardiology, Wenzhou People's Hospital, Wenzhou, Zhejiang, China.
authors: Wenbing
authors: W
authors: Jiang
authors: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Dongwu
authors: D
authors: Lai
authors: Department of Orthopedics, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Yan
authors: Y
authors: Ma
authors: Department of Orthopedics, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Ke
authors: K
authors: Zhou
authors: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Guosheng
authors: G
authors: Fu
authors: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Institute of Translational Medicine, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: shimingxu@zju.edu.cn.
authors: Shiming
authors: S
authors: Xu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008798:Mevalonic Acid / Q000378:metabolism*; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047428:Protein Kinase Inhibitors; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D008798:Mevalonic Acid; D002118:Calcium
keywords: Calcium handling; FK506-binding protein 12.6; Mevalonate pathway; Ryanodine receptor 2; Small GTPase