Hypoxia and the Renin-Angiotensin System in Atherosclerosis

Abstract

Background – Cardiovascular disease is the leading cause of morbidity and mortality worldwide and atherosclerosis is estimated to be the underlying cause of approximately 50% of all deaths in western societies. Many aspects of the atherosclerotic disease are still incompletely characterized; it is commonly believed that inflammation is the driving force in development and progression of the disease and lately here has been increasing interest in the possible interplay between hypoxia and inflammation as well as the renin-angiotensin system (RAS) and inflammation. Aim – To test the hypothesis that hypoxia leads to induction of the RAS, including angiotensin II receptor type 1 (AT₁), and that this results in increased inflammation in the atherosclerotic plaque. To investigate what cells would be involved in hypoxia-RAS interplay and to asses effects of RAS interfering drugs in hypoxic environments. Methods – Histological examination of human atherosclerotic plaques and comparative analysis of plaques and serum proteins in patients treated with RAS interfering drugs and controls. In vitro cell experiments conducted on primary human smooth muscle cells and macrophages where cells were exposed to hypoxia, angiotensin II and RAS interfering drugs. Results – Expression of AT₁ co localizes with expression of hypoxia marker HIF-1α in macrophage rich areas of atherosclerotic plaques. Statistical analysis proved strong correlation between expression of AT₁ and macrophage marker CD68 as well as between expression of HIF-1α and CD68. In vitro cell experiments confirmed expression of AT₁ in macrophages. Conclusions – This report presents evidence implicating hypoxia-RAS interplay via stabilization of the protein HIF-1α. Further experiments are required to elucidate what effect this interplay has on inflammatory profile of the atherosclerotic plaque.