Our broad objective is to establish that the natriuretic peptide system (NPS), via direct autocrine effects on the cardiomyocyte and paracrine effects on non-myocyte cardiac cells, is a key regulator of diastolic left ventricular (LV) function. Further, we propose to establish that enhancement of cardiomyocyte NPS activity represents a cardiac specific and effective therapeutic strategy to ameliorate the diastolic dysfunction associated with hypertensive heart disease. The heart failure (HF) syndrome is primarily related to diastolic dysfunction (diastolic HF, DHF) in 40-50% of cases. Therapies that specifically improve diastolic function in DHF are lacking. The natriuretic peptides (atrial and brain natriuretic peptide, ANP and BNP) stimulate production of the intracellular second messenger cGMP via binding to the natriuretic peptide A (NPRA) receptor. While traditionally viewed as circulating hormones that modulate volume and homeostasis and blood pressure via systemic effects, the presence of NPRA receptors on cardiomyocytes and on non-myocyte cardiac cells suggests the potential for autocrine/paracrine effects of the NPS on myocardial structure and function. We have performed preliminary studies utilizing cardiac specific transgenic models with positive and negative functional mutations in the NPRA. Based on our findings, we hypothesize that 1) the NPS enhances LV relaxation via a direct effect on cardiomyocyte function mediated by stimulation of cardiomyocyte NPRA receptors;2) the NPS reduces LV diastolic stiffness via direct effects on cardiac cardiomyocyte NPRA receptors which limit hypertrophy and effects on non-myocyte cardiac cells which limit fibrosis;3) therapeutic strategies based on cardiac specific augmentation of NPS actions improve diastolic function in established hypertensive heart disease in a dose dependent fashion;and 4) therapeutic strategies based on systemic augmentation of NPS levels improve myocardial and chamber diastolic properties via direct myocardial and indirect systemic effects. The proposed studies use cardiac specific transgenesis in mice to study the effect of the NPS directly on cardiomyocytes. Specifically, we will generate models that express gain of function (GOF-NPRA) or dominant negative (DN-NPRA) mutations in NPRA or over-express wild-type NPRA (NPRA) in cardiomyocytes. We will use both conventional and conditionally expressed cardiac specific transgenic models. The use of conditionally expressed transgenes will allow us to begin transgene expression after the establishment of hypertensive heart disease. Over-expression of wild-type NPRA will allow us to explore the dose response of cardiac specific augmentation of NPS actions. Studies are designed to address three specific aims: 1) Determine if the NPS alters LV diastolic function (relaxation and stiffness) and LV structure via effects mediated by cardiomyocytes NPRA;2) Determine if conditional over-expression of wild-type NPRA ameliorates diastolic dysfunction in established hypertensive heart disease;3) determine if chronic systemic administration of brain natriuretic peptide (BNP) ameliorates diastolic dysfunction in established hypertensive heart disease and if these effects are more robust in the presence of functional cardiac NPRA receptors.
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