Angiotensin (1-12) and Hypertension in the Elderly

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Project Summary The burden of high blood pressure, a major public health problem, is aggravated by an aging human population. A plethora of experimental data points to angiotensin II (Ang II), as the major contributing factor in the development of hypertension-related target organ damage. Although data suggested that classic RAS inhibitors exert positive therapeutic benefits multi-center studies of the long-term effects of these drugs on cardiovascular morbidity and mortality showed an effectiveness similar to other classes of antihypertensive drugs. Our hypothesis is that cardiac and renal Ang-(1-12), as a primary precursor for non-renin dependent Ang II generation, may account for the progressive development of pressure-related target organ damage. The major goal of this project is to evaluate the therapeutic effects of monoclonal antibodies (mABs) and cell penetrating nanobodies (Nbs) against the human sequence of Ang-(1-12) through combining high efficacy with improve treatment adherence. Work in progress characterized mAbs against the C-terminus of human Ang-(1-12). Whole animal hemodynamic experiments provide proof of concept on the ability of in vivo neutralization of Ang- (1-12). Research will be performed in a humanized model of hypertension engineered by insertion of the human angiotensinogen (AGT) gene into the genome of Sprague Dawley rats. Research strategies in male and female transgenic hypertensive rats will combine continuous blood pressure and heart rate recordings with assessment of plasma levels of Ang-(1-12), Ang I, Ang II, and Ang-(1-7), measurements of plasma renin activity, and serum aldosterone, and cardiac and renal function variables. These measures to be taken before and at 1 and 4 weeks after initiation of therapy with either Ang-(1-12) mAbs or nanobodies (NB). The effectiveness of this immunotherapy in blood pressure control will be further quantified in experiments in which antibodies are given to transgenic hypertensive rats in combination with lisinopril or valsartan. The proposed highly innovativestudies will provide a conceptual basis for novel hypertension treatment strategies involving neutralization of Ang-(1-12).