Pathophysiology of Extracellular Matrix and Desmin Breakdown in Volume Overload Heart

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The importance of the extracellular matrix loss in adverse LV remodeling is well established in the isolated pure volume overload of mitral regurgitation. Here the Principal Investigator reports a newly described breakdown of cardiomyocyte cytoskeletal protein desmin that adds an important intracellular structural defect with a direct impact on cardiomyocyte contractile function. This extracellular and intracellular protein breakdown mandates a novel medical therapy that enhances fibroblast extracellular matrix production and prevents desmin breakdown in order to prevent LV dilatation and heart failure. The novel findings of the current proposal are: 1) the ability of the highly destructive serine protease chymase to enter the cardiomyocyte via an endocytic mechanism, 2) the high chymase concentration within cardiomyocytes and fibroblasts in the heart, 3) evidence of chymase digestion of desmin in the heart with a pure volume overload, 4) evidence of chymase- mediated intracellular autophagic digestion of procollagen and fibronectin digestion in fibroblasts form the volume overloaded heart. It is well accepted that a pure volume overload is accompanied by excessive adrenergic drive. To complement the potential actions of chymase inhibitor, we have shown that β1-receptor blockade (β1-RB) improves calcium homeostasis and breakdown of the focal adhesion complex. We hypothesize that desmin and extracellular matrix breakdown are important therapeutic targets in volume overload that are responsive to a combined β1-RB and chymase inhibition that improves LV dilatation and function. In the series of aims, we will explore the intracellular (cardiomyocyte desmin) and extracellular (fibroblast autophagy) mechanisms of protein breakdown and resultant effects on LV remodeling and function. The mechanism of extracellular matrix loss and desmin breakdown in VO is multifactorial and here we propose novel mechanisms for a combined therapy of β1-RB and chymase inhibition that will target cardiomyocyte desmin breakdown (Aim 1) and fibroblast digestion of procollagen by autophagy (Aim 2), resulting in attenuation of LV dilatation and improvement in LV systolic function in the pure VO of ACF (Aim 3).