Metformin enhances nitric oxide production and diminishes Rho kinase activity in rats with hyperlipidemia

Abstract

BackgroundRho kinase over-activation is associated with nitric oxide (NO) reduction and atherosclerosis. Metformin is favorable for endothelial function improvement and cardiovascular outcomes. Whether cardio-protective effect of metformin is associated with Rho kinase activity is unknown.MethodsHyperlipidemia model of rats were established accordingly. Thereafter, medical interventions in terms of atorvastatin, metformin or combined therapy were administered for 4 weeks. Laboratory parameters were compared among each groups at initial, 6 weeks of high-fat and high-cholesterol diet administration, and 4 weeks of medical intervention. Lineal regression analyses were performed.ResultsNo significant difference of laboratory parameters was observed initially. Six weeks of high-fat and high-cholesterol diet administration, serum levels of cholesterol, C-reactive protein (CRP) level, and Rho kinase activity were significantly increased while NO production was concomitantly reduced in comparison to the sham group. After 4 weeks of medical intervention, CRP level and Rho kinase activity were profoundly diminished while NO production was significantly enhanced in the atorvastatin and metformin groups, and these benefits were further enhanced with combined therapy. Lineal regression analyses showed that Rho kinase activity was negatively correlated with NO production but positively correlated with CRP level.ConclusionIn rats with hyperlipidemia, metformin and atorvastatin therapy is favorable for NO production and CRP reduction, which might be associated with Rho kinase activity decrease.

Atorvastatin Plus Metformin Confer Additive Benefits on Subjects with Dyslipidemia and Overweight/Obese via Reducing ROCK2 Concentration

“…And results from previous researches also indicated that the cholesterol-independent benefits derived from statins therapy were at least partially dependent on ROCK inhibition [20,24,25]. Notably, consistent with experimental findings [15,26,27], data from our present clinical research also supported the concept that metformin has additional vascular-protective effects other than glucose-modulation. Compared to the control group, the variables including the rate of obese, Hs-CRP level, ROCK2 and NO concentrations were improved more profoundly in the combined group (p < 0.05).…”

“…And through inhibiting RhoA/ROCK signaling pathway, statins confer pleiotropic effects including endothelium-protection and anti-inflammation on cardiovascular system [13,14]. Interestingly and importantly, our recent findings indicated that through diminishing ROCK concentration, metformin administration enhanced NO production in rats with dyslipidemia [15]. Therefore, we hypothesized that statins plus metformin might provide additive benefits on NO production through their synergistic effects on reducing ROCK concentration.…”

Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients

“…Metformin improves vascular function via attenuation of IR/hyperinsulinemia [19], and can also decrease serum levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, by modulating androgen levels and insulin action [34]. In addition, metformin stimulates AMPK and phosphorylates endothelial nitric oxide synthase (eNOS) [19,35], while it enhances NO levels and diminishes Rho kinase in animal models of hyperlipidemia [36]. However, in the present study we have no detected differences in NO levels between control and PCOS subjects either in basal conditions or after metformin treatment.…”

The Effects of Pycnogenol® as Add‐on Drug to Metformin Therapy in Diabetic Rats

“…There is evidence, that metformin treatment activates AMPK signaling pathway and promotes phosphorylation of endothelial NO synthase (Liu et al ., ). Metformin increases α‐subunit activity of AMPK by its phosphorylation, as well as increase the expression of eNOS and thus increase the bioavailability of NO (Davis et al ., ).…”