Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

Abstract

Aim: Atherosclerosis is a cardiovascular disease; however, there is little information on signal transduction for vascular function in the early stage of atherosclerosis. In this work, we investigated the role of Rho/Rho-kinase and nitrogen oxide (NO)/cyclic GMP (cGMP) signaling pathways in the aorta prior to atherosclerosis. Methods: Tension, the expression of RhoA protein, Rho-kinase activity and the cGMP level were measured using endothelium-intact or -denuded aorta prepared from apolipoprotein E-deficient (apoE-KO) and C57BL/6 wild-type (WT) mice at 2 months of age. Results: Phenylephrine (PE) induced less maximal contraction in the endothelium-denuded aorta from apoE-KO than from WT mice. A Rho-kinase inhibitor (Y-27632) reduced more effectively the contraction of apoE-KO than WT mice, but their RhoA proteins and Rho-kinase activities were not so different. Acetylcholine caused larger relaxation of the PE-stimulated, endothelium-intact aorta in apoE-KO due to endothelial NO release than WT mice. The basal cGMP level in the endotheliumintact aorta of apoE-KO mice was higher than that of WT. Conclusions: Smooth muscle contraction via 1-adrenergic receptor shows higher dependency on Rho-kinase activity, suggesting down-regulation of the mechanism different from Rho/Rho kinase signaling in the aorta prior to atherosclerosis. Endothelium-dependent relaxation is also intensified through the NO/cGMP pathway.

Rho Kinases in Cardiovascular Physiology and Pathophysiology

“…Rho/ROCK pathway is substantially involved in inflammatory and arteriosclerotic arterial lesions in animals and humans (reviewed in references 16,168,169). Multiple studies in experimental models involving fasudil 170–172 and other ROCK inhibitors 173,174 have demonstrated that ROCK is a critical contributor to the inflammatory atherosclerotic process. ROCK inhibitors lead to up-regulation of eNOS and reduced endothelial dysfunction, 174,175 decreased vascular cell contraction, proliferation and migration, 174,176,177 decreased vascular oxidative stress, 178 decreased vascular inflammation, macrophage infiltration and foam cell formation, 171,173 and reduced arterial intima-medial thickness and atherosclerosis plaque formation.…”

Reduction of NO-mediated Relaxing Effects in the Thoracic Aorta in an Experimental Chronic Kidney Disease Mouse Model

“…Each strip of the aorta was placed in a 5-mL organ bath containing normal Krebs solution (Na 137.4, K 5.9, Mg 2 1.2, Ca 2 2.6, HCO3 15.5, H2PO4 1.2, Cl 134, glucose 11.5 mM; pH 7.4) bubbling with 95% O2 and 5% CO2. After an equilibration period of 60 minutes, the mechanical activity was measured via isometric recording under a resting tension of 300 mg 20) . PE was added in increments to study the concentration-dependent effects.…”

Neuroendocrine and Cardiac Metabolic Dysfunction and NLRP3 Inflammasome Activation in Adipose Tissue and Pancreas following Chronic Spinal Cord Injury in the Mouse

“…In fact, p38 activation is an intermediary of pro-inflammatory-induced tissue damage and the pathophysiology of heart disease (Kaiser et al, 2004; Kerkela and Force, 2006; Clark et al, 2007) and has been the target of therapeutic intervention strategies (Marber et al, 2010). Similarly, ROCK involvement in CVD comorbidities including hypertension (Mukai et al, 2001; Seko et al, 2003; Moriki et al, 2004), atherosclerosis (Rekhter et al, 2007; Mori-Kawabe et al, 2009; Wu et al, 2009) and cardiac hypertrophy and heart failure (Higashi et al, 2003; Satoh et al, 2003; Fukui et al, 2008; Phrommintikul et al, 2008), has been the focus of directed therapeutics. These efforts highlight the significance of these signaling pathways in CVD progression.…”