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Obesity is a major contributing feature of HFpEF. Lipid overload occurring in HFpEF alters the homeostasis of the UPR (unfolded protein response) signaling pathway in cardiomyocytes. We have previously shown that UPR alterations are major driver of HFpEF pathogenesis. Here we set to comprehensively understand the role of the PERK (PKR-like endoplasmic reticulum kinase) arm of the UPR in HFpEF. To gain insights into the role of lipid biology in HFpEF, we will investigate the role of a lipid-based post-translational modification (PTM), S-palmitoylation, in PERK regulation in cardiomyocyte. Moving forward, we will dissect mechanisms of PERK-dependent modulation of cardiomyocyte response in HFpEF after exercise training - one of the few known beneficial interventions in this syndrome. Focusing on the fundamental mechanisms of lipid response in HFpEF- cardiomyocyte, we will contribute to the understanding of the metabolic alterations in this syndrome providing insights of scientific, and potentially clinical, relevance.
Graphical Abstract: Modulation of endoplasmic reticulum response by PERK Palmitoylation in HFpEF and exercised hearts. Ad: Adenovirus. siRNA: short interference RNA
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