Gender Effects on Remodeling of Lipid and Sarcomere Dynamics in Hypertrophy

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DESCRIPTION (provided by applicant): Gender influences the pathogenesis of heart failure, despite no inherent differences in myocyte contractility. Both humans and animals show gender differences in lipid dynamics during pathophysiological stress. Yet, the role of gender, as a determinant of altered cardiac lipid, in the pathogenesis of cardiac decompensation is largely unknown. This research focuses on mechanisms invoked by gender, dietary fat, and stress via pressure overload, that alter the balance between mitochondrial oxidation and cellular storage of long chain fatty acids (LCFA) to affect myofilament biochemistry and activity. We will examine gender and estrogen effects on the remodeling of cardiac lipid dynamics in response to pressure overload, focusing on both active and passive components of heart function; the active component being biochemical changes within sarcomeric proteins, due to metabolic signaling, and the passive component being myocardial stiffness due to lipid infiltration. Preliminary data suggest lipid accumulation produces myocardial stiffness, and that gender influences cardiac lipid dynamics and acyl derivatives. We reported reduced triacylglyceride (TAG) turnover and contributions of TAG to mitochondrial oxidation in hypertrophied hearts and find that acyl-derivatives affect myofilament phosphorylation and sensitivity to Ca2+. We plan to combine in vivo measurements of cardiac function and lipid content, with stable isotope kinetics of metabolic flux and myofilament proteomics to address a two-fold hypothesis that: 1) Gender differences, due to estrogen, affect metabolic reprogramming in cardiac hypertrophy with shifts in lipid utilization/storage affecting cardiac function, and 2) that dietary fat, storage (PPAR� ovr expression) and uptake (FATP1 overexpression) reveal gender-specific changes in cardiac lipid dynamics, affecting myocardial compliance and sarcomere activity. Aims are: 1) Examine gender and estrogen-dependent differences in lipid utilization/storage dynamics in hearts of male, female, and overiectomized female, non-transgenic (NTG) and MHC-PPAR� low-overexpressing (strain 404-4) mice; 2) Test how LCFA uptake, gender and estrogen contribute to the response to pressure overload by determining a) lipid dynamics and consequential effects on myocardial 2-D strains, tissue stiffness and contractility and b) ceramide species and sphingosine production and consequential effects on myofilament phosphorylation, oxidation and Ca-responsiveness in hearts of non-transgenic mice and transgenic mice overexpressing FATP1; 3) Determine the potential for gender-based adaptations in TAG dynamics and LCFA oxidation rates in response to pressure overload, to affect a) myocardial 2-D strains and stiffness through mechanical effects of lipid accumulation and b) sarcomere activity through phosphorylation effects of LCFA-derived intermediates, ceramides and sphingosine, on myofilament sensitivity in MHC-PPAR� hearts. The objectives are to elucidate mechanisms for reprogramming cardiac lipid dynamics that affect heart function, thereby identifying strategies for early diagnosis and gender specific-treatment protocols to mitigate the development of cardiomyopathy.