Opposing Roles of Nitric Oxide and Rho-Kinase in Lipid Metabolism in Mice

Abstract

Dyslipidemia is a life-style disorder and is one of the important risk factors of cardiovascular diseases. Nitric oxide (NO) exerts beneficial effects on lipid metabolism through activation of hepatic sterol regulatory element-binding protein (SREBP)-2, a transcriptional factor for cholesterol metabolism and expression of LDL receptor, while Rho-kinase, an effecter protein of small G protein, RhoA, contributes to the pathogenesis of metabolic syndrome through suppressing the whole body energy consumption. However, the crosstalk between NO and Rho-kinase in regulation of lipid metabolism remains to be elucidated. In the present study, we used male wild-type (WT) mice and mice lacking three isoforms of NO synthase (NOSs −/− ). WT mice were fed either normal diet (ND) or high-fat diet (HFD), while NOSs −/− mice were fed ND with or without a selective Rho-kinase inhibitor, fasudil (100 mg/kg/day), for 6 weeks. At 6 weeks, plasma NOx concentration was significantly decreased and Rho-kinase activity and lipid levels were significantly elevated in HFD-fed WT mice and NOSs −/− mice compared with ND-fed WT mice. In the liver, SREBP-2 activity was reduced in NOSs −/− mice. Fasudil ameliorated lipid levels in HFD-fed WT mice and NOSs −/− mice without affecting SREBP-2 activity or LDL receptor expression, whereas it significantly enhanced phosphorylation of AMP-activated kinase (AMPK) in the liver and skeletal muscle. Importantly, the beneficial metabolic effects of fasudil were absent in HFD-fed AMPK −/− mice. These results provide the first evidence that NO and Rho-kinase play opposing roles for the lipid metabolism, suggesting that Rho-kinase inhibitors could be novel therapeutic agents of dyslipidemia.

RhoA/Rho-Kinase in the Cardiovascular System

“…55,56 Rho-kinase-deficient mice revealed preserved EC function in a diabetic model. 56 Moreover, a Rho-kinase inhibitor, fasudil, significantly enhanced the 57,58 Statins upregulate eNOS by cholesterolindependent mechanisms, involving the inhibition of Rho geranyl-geranylation. 59 In addition, small GTP-binding protein dissociation stimulator plays a central role in the pleiotropic effects of statins, independently of the Rho-kinase pathway.…”

Rho GTPases—Emerging Regulators of Glucose Homeostasis and Metabolic Health

“…RhoA might also regulate glucose homeostasis, as pharmacological inhibition of RhoA’s target, ROCK, using Fasudil prevented high-fat diet-induced hypercholesterolemia and glucose intolerance in mice [156]. Furthermore, body weight, serum lipid levels, and glucose metabolism were improved in mice with whole body overexpression of a dominant-negative ROCK, compared with littermate control mice [116].…”

Comparison of the measured pre‐ejection periods and left ventricular ejection times between echocardiography and impedance cardiography for optimizing cardiac resynchronization therapy

“…The parameters measured by the two methods were compared with the paired t‐test. Relationships between the variables were analyzed by Spearman's correlation coefficient analysis [7]. Statistical analysis was performed with IBM SPSS Statistics, version 21 (IBM Corp., Armonk, NY, USA).…”