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Targeting HDAC6 to treat heart failure with preserved ejection fraction, Mouse heart LC-MS with PTMscan

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in HFpEF mouse models. Additionally, in mice lacking the Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and their combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts heart pathophysiology and is a promising target for HFpEF treatment.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Cardiac Muscle Cell

DISEASE(S): Diastolic Heart Failure

SUBMITTER: Farshad Farshidfar

LAB HEAD: Farshad Farshidfar

PROVIDER: PXD048363 | Pride | 2024-01-17

REPOSITORIES: Pride

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