Perillaldehyde prevents the formations of atherosclerotic plaques through recoupling endothelial nitric oxide synthase

Abstract

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is essential for cardiovascular homeostasis owing to its anti-inflammatory, antithrombotic, antiproliferative, and antioxidant effects. Perillaldehyde (PAH), one of the major oil components in Perilla frutescens, has anti-inflammatory effects. This study was designed to explore whether PAH prevents atherosclerosis through normalizing eNOS functions. The model of atherosclerosis was induced by feeding rats and mice with high-fat diet or plus balloon injury. Oil red and hematoxylin-eosin (HE) stainings were used to assess the atherosclerotic plaque. Pretreatment of PAH for 30 minutes concentration-dependently increased tetrahydrobiopterin (BH4) levels, NO generations, and improved cell viabilities in cultured human umbilicus vessel endothelial cells (HUVEC) incubated with oxidized (OX) low-density lipoprotein (LDL), in which all protective effects of PAH were abolished by guanosinetriphosphate (GTP) cyclohydrolase 1 inhibitor 2,4-Diamino-6-hydroxypyrimidine (DAHP) or eNOS inhibitor L-NAME in those cells. In rats, high-fat diet plus balloon injury induced the formation of atherosclerotic plaque in carotid arteries. Administration of PAH or lovastatin reduced the size of atherosclerotic plaque in rats and improved the responses of aortic rings to acetylcholine isolated from rats, accompanied with increased BH4 content and NO generations. In Apoe -/- mice feeding with normal diet or high-fat diet, PAH (150 mg/kg) reduced the size of atherosclerotic plaque in aortic arteries, prevented endothelial dysfunctions, and increased both BH4 and NO generations in carotid arteries. PAH prevents the growth of atherosclerosis through increasing BH4 generation and subsequent eNOS recouping. Clinically, PAH should be considered as a new medicine to treat patients with atherosclerosis.