Published Online
on July 9, 2007

A more recent version of this article appeared on July 31, 2007

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Submitted on June 28, 2006
Accepted on May 29, 2007

Enhanced External Counterpulsation Inhibits Intimal Hyperplasia by Modifying Shear Stress-Responsive Gene Expression in Hypercholesterolemic Pigs

Yan Zhang MD, Xiaohong He PhD, Xiaolin Chen MD, PhD, Hong Ma MD, Donghong Liu MD, Jinyun Luo MD, Zhimin Du MD, Yafei Jin MD, PhD, Yan Xiong MD, Jiangui He MD, PhD, Dianqiu Fang BS, Kuijian Wang PhD, William E. Lawson MD, John C.K. Hui PhD, Zhensheng Zheng MD, and Guifu Wu MD, PhD^*

From the Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China (Y.Z., X.H., X.C., H.M., D.L., J.L., Y.J., Y.X., D.F., Z.Z., G.W.); Division of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (H.M., Z.D., Y.J., J.H., Z.Z., G.W.); Cardiovascular Research Institute, Sun Yat-sen University, Guangzhou, China (H.M., Z.D., J.H., Z.Z.); Division of Ultrasound, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (D.L.); Department of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China (K.W.); and Division of Cardiology, State University of New York at Stony Brook (W.E.L., J.C.K.H.).

^* To whom correspondence should be addressed. E-mail: eecplab{at}163.com.

Background--Enhanced external counterpulsation (EECP) is a circulation assist device that may improve endothelial dysfunction by increasing shear stress. Chronic exposure of vascular endothelial cells and vascular smooth muscle cells to relatively high physiological shear stress has antiproliferative and vasoprotective effects. The present study hypothesizes that EECP inhibits intimal hyperplasia and atherogenesis by modifying shear stress-responsive gene expression.

Methods and Results--Thirty-five male pigs were randomly assigned to 3 groups: high-cholesterol diet (n=11), high-cholesterol diet plus EECP (n=17), and usual diet (control; n=7). The coronary arteries and aortas were collected for histopathological study and immunohistochemical and Western blot analysis. The peak diastolic arterial wall shear stress during EECP increased significantly compared with before EECP (49.62±10.71 versus 23.92±7.28 dyne/cm²; P<0.001). Intimal hyperplasia was observed in the coronary arteries of the high-cholesterol diet group, whereas in animals receiving EECP, the intima-to-media area ratio was significantly decreased by 41.59% (21.27±10.00% versus 36.41±16.69%; P=0.008). Hypercholesterolemia attenuated the protein expression of endothelial NO synthase and enhanced the phosphorylation of extracellular signal-regulated kinases 1/2. EECP treatment alleviated these adverse changes.

Conclusions--EECP reduces hypercholesterolemia-induced endothelial damage, arrests vascular smooth muscle cell proliferation and migration, decreases proliferating cell nuclear antigen proliferative index, suppresses extracellular matrix formation, and eventually inhibits intimal hyperplasia and the development of atherosclerosis by increasing the arterial wall shear stress, which in turn activates the endothelial NO synthase/NO pathway and probably suppresses extracellular signal-regulated kinases 1/2 overactivation.

Key words: atherosclerosis • endothelium • hypercholesterolemia • nitric oxide synthase • remodeling

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