Kiyoshi Ozumi

Statin Treatment Upregulates Vascular Neuronal Nitric Oxide Synthase Through Akt/NF-κB Pathway

Objective—Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are known to enhance vascular expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS). In this study, we examined whether statins also upregulate vascular expression of neuronal NOS (nNOS). Methods and Results—In cultured rat aortic smooth muscle cells, treatment with atorvastatin significantly increased nNOS expression, associated with activation of Akt and NF-&kgr;B. Inhibition of Akt by dominant-negative Akt suppressed atorvastatin-induced nNOS expression as well as Akt and NF-&kgr;B activation. Inhibition of NF-&kgr;B by dominant-negative I&kgr;B also attenuated atorvastatin-induced nNOS expression and NF-&kgr;B activation, but not Akt activation. We further examined whether atorvastatin also enhances nNOS expression in isolated mouse aorta, and if so, how much nNOS-derived NO accounts for atorvastatin-induced NOx production. In isolated aortas of wild-type mice, atorvastatin significantly increased all three NOS isoform expression and NOx production. In isolated aortas of doubly i/eNOS−/−, n/eNOS−/−, and n/iNOS−/− mice, which express only nNOS, iNOS, and eNOS, respectively, atorvastatin-induced NOx production was approximately 25%, 25%, and 50% to that of wild-type mice, respectively, suggesting that nNOS accounts for 25% of the atorvastatin-mediated NOx production. Conclusions—These results indicate that atorvastatin upregulates vascular nNOS through Akt/NF-&kgr;B pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.

Oxidized low-density lipoprotein-induced apoptosis is attenuated by insulin-activated phosphatidylinositol 3-kinase/Akt through p38 mitogen-activated protein kinase.

1.u2002The aim of the present study was to investigate whether p38 mitogen‐activated protein kinase (p38 MAPK) is involved in oxidized low‐density lipoprotein (oxLDL)‐induced apoptosis of human umbilical vein endothelial cells (HUVECs). We also sought to determine whether this apoptosis is regulated by the phosphatidylinositol 3‐kinase (PI3K)/Akt pathway.

Evaluation of Improved Coronary Flow Velocity Reserve Using Transthoracic Doppler Echocardiography After Single LDL Apheresis

Abstract:u2002 The purpose of this study was to clarify whether coronary flow velocity reserve (CFVR), evaluated by adenosine 5′‐triphosphate‐induced hyperemia, is improved by single low‐density lipoprotein (LDL) apheresis. Lipid lowering therapy is known to improve endothelium‐dependent vasodilatation in forearm or coronary resistant vessels. However, few reports have studied the effect of acute LDL reduction on CFVR. Methods: Seven patients with familial hypercholesterolemia and significant coronary stenosis except in the left anterior descending artery (LAD) were enrolled in this study. Coronary flow velocity reserve was estimated before and after LDL apheresis using transthoracic Doppler echocardiography (TTDE), which detects the flow velocity at the distal site of the LAD. Although the averaged diastolic peak velocity (ADPV) during ATP‐induced hyperemia was similar before and after LDL apheresis, the ADPV at baseline decreased from 30.69 to 25.56u2003cm/s, resulting in an increased CFVR from 1.78 to 2.10 (Pu2003<u20030.001). Plasma bradykinin and 6u2003ketou2003PGF1α increased while fibrinogen and plasma viscosity decreased after apheresis. Single LDL apheresis improves CFVR according to TTDE analysis because of the decreasing ADPV at baseline, which is thought to be induced by epicardial coronary artery dilatation and improved microvessel function. This is the result of various factors, such as changes in plasma LDL cholesterol, bradykinin and PGI2 levels with LDL apheresis.