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Browsing by Author "Moravec, Christine S."
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Item Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover(Springer Nature, 2021-05-19) Martin, Thomas G.; Myers, Valerie D.; Dubey, Praveen; Dubey, Shubham; Perez, Edith; Moravec, Christine S.; Willis, Monte S.; Feldman, Arthur M.; Kirk, Jonathan A.; Pathology and Laboratory Medicine, School of MedicineThe association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.Item Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure(Springer Nature, 2019-06-24) Cordero, Pablo; Parikh, Victoria N.; Chin, Elizabeth T.; Erbilgin, Ayca; Gloudemans, Michael J.; Shang, Ching; Huang, Yong; Chang, Alex C.; Smith, Kevin S.; Dewey, Frederick; Zaleta, Kathia; Morley, Michael; Brandimarto, Jeff; Glazer, Nicole; Waggott, Daryl; Pavlovic, Aleksandra; Zhao, Mingming; Moravec, Christine S.; Tang, W. H. Wilson; Skreen, Jamie; Malloy, Christine; Hannenhalli, Sridhar; Li, Hongzhe; Ritter, Scott; Li, Mingyao; Bernstein, Daniel; Connolly, Andrew; Hakonarson, Hakon; Lusis, Aldons J.; Margulies, Kenneth B.; Depaoli-Roach, Anna A.; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas; Ashley, Euan A.; Biochemistry and Molecular Biology, School of MedicineHeart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.