Hemodynamic stimuli set in motion a sequence of biochemical and inflammatory events in the cardiac interstitial fluid (ISF) space that interact with cell surface molecules to dictate extracellular matrix (ECM) turnover with subsequent maladaptive myocyte orientation, elongation, hypertrophy and apoptosis. In hearts with volume overload (VO), a continual state of remodeling of myocyte and ECM results in a progressive LV dilatation, decreased collagen deposition (in spite of increased cardiac angiotensin II (ANG II) expression), increased LV wall stress, and congestive heart failure (HF). However, we and others have shown that blockade of the renin-angiotensin system does not improve VO cardiac hypertrophy. We have rigorously defined the temporal progression of VO HF in the rat subjected to aortocaval fistula (ACF). These studies have characterized 3 key, clinically relevant, time points: acute (6 hrs-5 days), chronic compensated (4-8 wks) and chronic decompensated (15-21 wks). We found mast cell infiltration and protease activation (chymase, cathepsin G) associated with MMP activation, ECM degradation, and iNOS-dependent protein nitration within 6-12 hrs. ECM degradation persisted and ISF BK (10) and LV BK2 and LV fibroblast AT2 receptor expression were increased during VO. Treatment with BK2 receptor antagonist for only 2 days after ACF was sufficient to prevent mast cell infiltration, iNOS-dependent protein nitration, and ECM degradation at 5 days and 4 wks of ACF, while attenuating LV remodeling. This led to the hypothesis that acute and chronic increases in ISF BK with VO underlies the adverse LV and cardiomyocyte remodeling initiated by its early effect on inflammation and subsequently perpetuated by its effect on cardiac fibroblast signaling and function. In this proposal, AIM 1 will determine whether BK mediates ECM degradation and LV and cardiomyocyte remodeling during the progression of VO using in-vivo microdialysis to measure ISF BK and ANG I1.
AIM 2 will determine the mechanisms by which ISF BK is elevated during VO.
Aim 3 will determine the mechanisms by which BK alters cardiac fibroblast signaling and expression of ECM modulatory proteins during the progression ACF. These studies will uncover new mechanistic insights and therapeutic strategies for VO.
