Objective-Rho-Kinase activity is increased in cardiovascular diseases and in patients with cardiovascular risk factors.However, it is not known whether inhibition of Rho-kinase could lead to cardiovascular protection and, if so, by what mechanism. Methods and Results-In human endothelial cells, the Rho-kinase inhibitor, hydroxyfasudil (HF) (1 to 100 mol/L), increased Akt serine-473 phosphorylation within 15 minutes, leading to a 2.2-fold and 4.0-fold increase in Akt kinase activity and nitric oxide (NO) release, respectively. Activation of Akt and eNOS by HF was completely blocked by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002 (10 mol/L). To determine the physiological relevance of this pathway, we used 2 models of ischemia-reperfusion (I/R) injury. Acute administration of fasudil (10 mg/kg, intraperitoneal, 1 hour before ischemia) decreased leukocyte recruitment and adhesion to the mesenteric endothelium after I/R injury in wild-type but not eNOS Ϫ/Ϫ mice. Similarly, treatment with fasudil decreased myocardial infarct size by 38% in rats subjected to transient coronary artery occlusion. Cotreatment with 2 PI3-kinase inhibitors, wortmannin and LY294002, or the eNOS inhibitor, L-NAME, blocked the cardiovascular protective effects of fasudil. Conclusions-Inhibition of Rho-kinase leads to the activation of the PI3-kinase/Akt/eNOS pathway and cardiovascular protection. These findings suggest that Rho-kinase may play an important role in mediating the inflammatory response to I/R injury.
Abstract-The vascular endothelium is a dynamic endocrine organ that regulates contractile, secretory, and mitogenic activities in the vessel wall and hemostatic processes within the vascular lumen. Risk factors for cardiovascular disease, such as cigarette smoking, hypertension, and elevated serum lipid levels, impair endothelial function and lead to the development of atherosclerotic vessels. Recent studies suggest that statins reduce cardiovascular events in part by improving endothelial function. Statins reduce plasma cholesterol levels, thereby decreasing the uptake of modified lipoproteins by vascular wall cells. There is increasing evidence, however, that statins may also exert effects beyond cholesterol lowering. Indeed, many of these cholesterol-independent or "pleiotropic" vascular effects of statins appear to involve restoring or improving endothelial function through increasing the bioavailability of nitric oxide, promoting re-endothelialization, reducing oxidative stress, and inhibiting inflammatory responses. Thus, the endotheliumdependent effects of statins are thought to contribute to many of the beneficial effects of statin therapy in cardiovascular disease. Key Words: 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor Ⅲ endothelium Ⅲ atherosclerosis Ⅲ cholesterol Ⅲ protein kinase Akt T he vascular endothelium is the inner lining of blood vessels and serves as an important autocrine/paracrine organ that regulates vascular wall contractile state and cellular composition. Because of its strategic location between the circulation and the vascular wall, the endothelium interacts with both cellular and hormonal mediators from these two compartments. There is growing evidence that endothelial dysfunction, which is often defined as the decreased synthesis, release, and/or activity of endothelial-derived nitric oxide (NO), is an important factor leading to atherosclerosis and acute coronary syndromes. 1,2 This realization, in part, is based on the fact that the lack of NO in atherosclerotic vessels contributes to impaired vascular relaxation, 3 platelet aggregation, 4 increased vascular smooth muscle proliferation, 5 and enhanced leukocyte adhesion to the endothelium. 6 Indeed, vasoconstriction, platelet activation, and thrombosis caused by the rupture of atherosclerotic plaques are primary features of acute coronary syndromes and other cardiovascular events. 7 In addition to endothelial dysfunction, another important feature of atherosclerotic vessels is endothelial cell activation. 8 The activated endothelium expresses cell-surface adhesion molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial-leukocyte adhesion molecule, which facilitate the attachment of circulating leukocytes to the endothelium. 9 Monocyte adhesion to the vessel wall and its subsequent differentiation into macrophages are crucial events leading to the development of macrophage-derived foam cells in atherosclerotic plaques. Cytokines, oxidized LDLs (ox-LDLs), and infectious a...
RPC activates myocardial PKCepsilon through a neuronal and bradykinin-dependent pathway. We assume that activation of PKCepsilon is an important step in cardioprotection induced by remote preconditioning.
MTH in combination with primary PCI is feasible and safe in patients resuscitated after cardiac arrest due to acute myocardial infarction. A combination of these therapeutic procedures should be strongly considered as standard therapy in patients after out-of-hospital cardiac arrest due to STEMI.
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