No abstract

No abstract

No abstract

BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.Methods and ResultsExperimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.ConclusionsRho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp dynamically. 6 Under normal conditions, smaller and crescentshaped RV wall thickness is only one-fifth of that of the LV, and the RV has a higher proportion of the α-myosin heavy chain isoform that results in a more rapid but less energy efficient contraction. 7 Furthermore, coronary blood flow to the RV is roughly balanced between systolic and diastolic time periods, while a majority of the flow occurs in the diastole in the LV wall. 8 The RV has greater resistance to ischemia compare to the LV and has better adaptation to volume overload states, while LV has better adaptation to pressure overload states. 9 Thus, the increase in RV afterload might not be similar to that in the LV in response to pharmacological therapies. 10 Nitric oxide (NO) synthesized by endothelial cells (eNOS) is an important downstream signaling molecule in the cardiovascular system. 11 The protective effects of NO on vascular ulmonary hypertension (PH) is a fatal disease characterized by increased pulmonary vascular resistance, resulting in an impaired right ventricular (RV) function due to increased RV afterload and contractile abnormality of the RV. 1-3 The disease is progressive in nature, leading to RV hypertrophy (RVH) and ultimately RV failure and death within less than 5 years after diagnosis. 1,4 Mortality of PH patients is closely associated with alterations in RV hemodynamic variables, such as mean pulmonary artery pressure, mean right atrial pressure and cardiac index. 4 Despite the recent advances in medical therapy for PH, there is no cure for the disorder, and cellular and molecular mechanisms of RV remodeling and failure in PH still remain to be fully elucidated. 5 RV is different from left ventricle (LV) embryologically, macroscopically, ultrastructurally, biochemically and hemo- Background: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the mechanisms of RV remodeling in PH remain to be fully elucidated.