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 ?1-receptor blockade (?1-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 ?1-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 ?1-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).
Heart disease is the number one cause of death in Americans including veterans. Every aspect of medical care in the VA medical system is affected by its common presence. Mitral regurgitation creates a unique stress to the heart by the regurgitation of blood backwards into the left atrium with contraction of the heart. The impetus for the current proposal emanated from the fact that there is no effective medical therapy for this condition that affects more than 6 million Americans. The Principal Investigator has now identified new mechanisms of cardiac damage and proposes a novel combination therapy in this grant that targets these processes. Our study will uncover new targets that lead to improved therapeutic strategies for the management of patients with mitral regurgitation that will prevent heart failure and improve outcomes from surgery to repair or replace the mitral valve, represents a major risk to our Veteran patient population.
| Dell'Italia, Louis J; Collawn, James F; Ferrario, Carlos M (2018) Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling. Circ Res 122:319-336 |
| Dell'Italia, Louis J (2017) Impact of VA Research on Health Care for All: Contributions Over Nine Decades and Counting. Circ Res 121:16-18 |
| Ahmed, Mustafa I; Guichard, Jason L; Soorappan, Rajasekaran Namakkal et al. (2016) Disruption of desmin-mitochondrial architecture in patients with regurgitant mitral valves and preserved ventricular function. J Thorac Cardiovasc Surg 152:1059-1070.e2 |
