Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway.
Statins are the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that function as potent inhibitors of cholesterol biosynthesis and have been used for many years for the treatment of hypercholesterolemia. However, accumulating experimental and clinical studies have revealed that the health benefits associated with statins treatment, particularly those conferred on the cardiovascular system, were the cholesterol-independent. Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important postranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. The isoprenylation of Rho is a prerequisite for Rho activation, facilitating its interaction with the plasma membrane, undergoing GDP-GTP exchange and be activated. Inhibition of RhoA geranylgeranylation by statins decreases membrane GTP-bound active RhoA and subsequent Rho-kinase activity. Activated RhoA via its downstream effector Rho-kinase is involved in a wide range of cellular functions, such as cell migration, proliferation and apoptosis. Recently, rising evidences suggested that RhoA/Rho-kinase pathway was essentially involved in various models of pulmonary hypertension and statins effectively ameliorated pulmonary hypertension. Based on this findings, we hypothesis that statins attenuate pulmonary hypertension via RhoA/Rho-kinase signaling pathway in vivo.
Xing
Xi-Qian
XQ
Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Middle Renmin Road, No. 86, Changsha, Hunan 410011, PR China.
Gan
Ye
Y
Wu
Shang-Jie
SJ
Chen
Ping
P
Zhou
Rui
R
Xiang
Xu-Dong
XD
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein