Hypertension is a major risk factor for development of cardiovascular disease. Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in this pathological process, since blocking the RAAS with ACEi or AT1-ant significantly improves cardiac function, regresses LV remodeling and prolongs survival in patients with cardiovascular disease. Besides RAAS inhibition, kinins and NO have been shown to participate in the cardioprotective effects of ACEi. During AT1 inhibition, activation of the AT2 receptor may also lead to the release of NO, either directly or via kinins. Here we propose to test the general hypothesis that Ang II acts locally in the heart via the AT1 receptor independently of its systemic effect, resulting in cardiac remodeling and dysfunction. We also hypothesize that in the heart Ang II acts either directly or via release of endothelin (ET), reactive oxygen species (ROS) and nuclear factor-kappa beta (NF-kappa beta), promoting inflammation, and these effects are mediated via the AT1 receptor. Kinins, NO and activation of the AT2 receptor antagonize the cardiac effects of Ang II. We propose to use a combination of molecular, physiological, and pharmacological approaches and several lines of bioengineered mice to test these hypotheses.
In Aim 1, we will use transgenic mice overexpressing Ang II in the heart to study whether 1) increased Ang II in the heart causes cardiac remodeling and dysfunction without increasing BP, and these local effects are mediated by release of ET, ROS and NF-kappa beta, in turn stimulating proinflammatory processes; and 2) in the presence of a hemodynamic load, Ang II in the heart accelerates cardiac remodeling and dysfunction.
In Aim 2, we will use transgenic mice overexpressing the AT2 receptor in the heart and AT2 receptor knockout mice to test the hypothesis that AT2 receptors expressed in the heart have a cardioprotective effect which is partially mediated by release of kinins and NO. We will further study whether activation of AT2 receptors increases kinins via stimulation of kininogenases other than tissue kallikrein.
In Aim 3, using bradykinin B2 receptor knockout mice (B2 -/-), we will test the hypothesis that expression of the B1 receptor is increased in the heart and vascular tissue in hypertension and myocardial infarction (MI), which may have an important vasodepressor and anti-trophic role. Dual blockade of B1 and B2 receptors may accelerate development of hypertension and LV hypertrophy and worsen cardiac remodeling and dysfunction in mice with MI.
In Aim 4, using eNOS -/-, nNOS -/- and iNOS -/- as well as double knockout (e/nNOS -/-) mice, we will test the hypothesis that NO released from eNOS and nNOS has a cardioprotective effect, while NO released from iNOS (which produces high amounts of NO) has a detrimental effect on the heart, especially when ROS formation is increased. These studies are significant, since they will demonstrate whether or not Ang II has a direct effect in the heart and whether these effects are antagonized by activation of the AT2 receptor, kinins and NO. These studies could lead to better treatment of target organ damage in hypertension.
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