Integrated Mechanisms of Cardiac Maladaptation

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DESCRIPTION (provided by applicant): Our program project addresses the mechanism of processes triggered by stresses on the heart that are adaptive and compensate for the stressor or are maladaptive and exacerbate the stressor leading to decompensation, heart failure and sudden death. The theme of our program is couched in the following hypothesis: Heart failure and sudden death commonly instigated by hypertension, coronary artery disease, and sarcomeric mutations induce altered signaling, remodeling, and function at the level of the myofilaments and that interventions operating at the level of the sarcomeres represent an important therapeutic approach. The program consists of three highly interactive and synergistic projects testing the overall hypothesis with diverse but meshing perspectives. Projects are supported by 3 Cores: Administrative, Human Cell and Tissue, and Proteomics and Analytical Biochemistry. Project 1 (Solaro) focuses on maladaptive and adaptive responses of cardiac function to novel signaling through angiotensin (Ang II) receptor (AT1R) and β-arrestin to sarcomeric proteins. The aims address the hypothesis that signaling via β-arrestin induces alterations in myofilament Ca-response that increases contractility and is therapeutically effective in acquired and familial DCM. Project 2 (Russell) proposes innovative experiments with microstructures of varying stiffness in testing the hypothesis that sarcomeric actin assembly depends on posttranslational modification (PTM) of proteins regulated by external cues signaling via mechano-transduction pathways. The experiments employ bioengineered micro-rods and magnetic micro-magnets to establish baseline values, and then test whether specific mechanisms of local actin assembly are via interaction of PKC-ε, HDAC3 and PIP2 with the actin capping protein CapZ. Project 3 (de Tombe) proposes experiments testing the hypothesis that human cardiac ventricular myosin light chain 2 (vMLC2) is a critical regulator of myocyte dynamics, which is poorly regulated in heart failure HF. The objective is to investigate MLC2 phosphorylation as a critical regulator of myocyte contraction and that increasing MLC2v phosphorylation with MLCK can partially reverse the dysfunction. Our approaches include novel mechanisms of signaling to and from the sarcomeres with a focus on translation of our findings to therapies for acquired and genetic cardiomyopathies.