Effect of HMBG1 on blood pressure and vascular function in hypertension: does sex matter?

Hypertension affects ~33% of adults in the U.S. and is an important risk factor for cardiovascular disease. Males and females both develop hypertension; although males typically have higher blood pressure (BP) and develop hypertension at younger ages than females. Basic science research has focused almost exclusively on males; valuable insight into disease progression and treatment which would be gained by studying females has been ignored. A critical barrier to improving BP control rates is lack of knowledge regarding molecular mechanisms driving BP elevation in either sex. Inflammation contributes to hypertension and organ damage in males; data in females are lacking. The molecular mechanisms that initiate the inflammatory response or how an immune response regulates BP or vascular function in either sex remain unknown. Our goal is to improve knowledge of the molecular mechanisms driving endothelial activation and immune cell infiltration in hypertension. High mobility group box 1 protein (HMGB1) is an endogenous 'danger molecule' that acts as a chemo-attractant for immune cells, up-regulates endothelial adhesion molecule expression and contributes to endothelial dysfunction. The impact of HMGB1 on the immune profile in hypertensive males and females or the role of HMGB1 in BP regulation or vascular function is unknown. Based on our preliminary data, our central hypothesis is that hypertensive males have greater HMGB1 release than females, which drives endothelial cell activation and T cell infiltration resulting in endothelial dysfunction and greater increases in BP. Spontaneously hypertensive rat (SHR) will be used to test our hypothesis in two specific aims. Aim 1 will test the hypothesis that greater HMGB1 levels in males results in higher BP and endothelial dysfunction relative to females. Male and female SHR will be treated with HMGB1 neutralizing antibody and BP and vascular function will be assessed. Aim 2 will test the hypothesis that greater HMGB1 levels in male SHR results in greater adhesion molecule expression and inflammatory T cell infiltration relative to females. Male and female SHR will be treated with HMGB1 neutralizing antibody and endothelial cell activation and the immune profile will be measured. The proposed studies, integrating physiological, pharmacological, and molecular techniques, will determine if HMGB1 is a novel target in hypertension that may improve BP control and vascular function in males and females. (AHA Program: Grant-in-Aid)