Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress

doi:10.1073/pnas.0500998102

Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress

^*Departments of General Pathology, Medicine, Human Pathology, and Clinical Pathology, School of Medicine, University of Naples, 80131 Naples, Italy; ^¶Excellence Research Center of Cardiovascular Diseases II, University of Naples (SUN), 80138 Naples, Italy; ^†Division of Anesthesiology and ^∥Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; ^‡Division of Hypertension, Mayo Clinic Foundation, Rochester, MN 55095; ^§Department of Anesthesiology, University of Novara, 28100 Novara, Italy; and ^‡‡Evans Department of Medicine, Boston University, Boston, MA 02118

Contributed by Louis J. Ignarro, February 5, 2005

Abstract

Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p-JUN) in the endothelium. Evidence suggests that polyphenolic antioxidants contained in the juice derived from the pomegranate can contribute to the reduction of oxidative stress and atherogenesis. The aim of the present study was to evaluate the effects of intervention with pomegranate juice (PJ) on oxidation-sensitive genes and endothelial NO synthase (eNOS) expression induced by high shear stress in vitro and in vivo. Cultured human coronary artery endothelial cells (EC) exposed to high shear stress in vitro and hypercholesterolemic mice were used in this study. PJ concentrate reduced the activation of redox-sensitive genes (ELK-1 and p-JUN) and increased eNOS expression (which was decreased by perturbed shear stress) in cultured EC and in atherosclerosis-prone areas of hypercholesterolemic mice. Moreover, oral administration of PJ to hypercholesterolemic mice at various stages of disease reduced significantly the progression of atherosclerosis. This experimental study indicates that the proatherogenic effects induced by perturbed shear stress can be reversed by chronic administration of PJ. This approach may have implications for the prevention or treatment of atherosclerosis and its clinical manifestations.

Footnotes

↵ †† To whom correspondence may be addressed. E-mail: lignarro{at}mednet.ucla.edu, claunap{at}tin.it, or claunap{at}bu.edu.
↵ ** This work was funded by a grant from the Lynda and Stewart Resnick Revocable Trust to L.J.I. and C.N. Lynda and Stewart Resnick own the POM Wonderful Company, for which L.J.I. is a consultant.
Author contributions: F.d.N., V.S., L.J.I., and C.N. designed research; F.d.N., S.W.-I., L.O.L., E.C., C.B., G.M., F.P.D., G.D.R., and V.S. performed research; E.C. contributed new reagents/analytic tools; F.d.N., S.W.-I., L.O.L., E.C., C.B., G.M., F.P.D., G.D.R., V.S., L.J.I., and C.N. analyzed data; and F.d.N., L.O.L., G.D.R., L.J.I., and C.N. wrote the paper.
Abbreviations: NOS, NO synthase; eNOS, endothelial NOS; EC, endothelial cells; PJ, pomegranate juice; p-JUN, phosphorylated form of JUN.