Abstract Body: Introduction: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases. Recent studies have demonstrated efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of HFpEF; however, patients with HFpEF still demonstrate significant risk of hospitalization and mortality, demonstrating the need to elucidate new therapeutic targets. Due to the contribution of metabolic syndromes in the pathophysiology of HFpEF, we aimed to study the role of phosphoglycolate phosphatase (PGP) in the development of HFpEF. We hypothesize that PGP is a metabolic repair enzyme that eliminates toxic metabolic intermediates and participates in DNA repair pathways to mitigate and reduce the cardiac stress induced by HFpEF.
Methods: To test the functional role of PGP in cardiomyocytes (CMs) response to HFpEF, we utilized the two-hit model to induce HFpEF in control (PGP^+/+ αMHC^Cre/+) or inducible PGP phosphatase inactive (PGP^D34N/D34N) crossed to the cardiomyocyte-specific alpha-myosin heavy chain Cre (PGP^D34N/D34N αMHC^Cre/+) mice, to inhibit PGP phosphatase activity. Mice were given the endothelial nitric oxide synthase (eNOS) inhibitor, L-NAME, in drinking water and fed a high-fat diet consisting of 60% kilocalories from fat for 15 weeks. Diastolic function was assessed by echocardiography, and insulin and glucose tolerance were measured.
Results: Compared to normal diet, both PGP^+/+ αMHC^Cre/+ and PGP^D34N/D34N αMHC^Cre/+ mice fed the HFpEF diet for 15 weeks weighed significantly more, indicative of developing HFpEF; no difference in the weight between PGP^+/+ αMHC^Cre/+ or PGP^D34N/D34N αMHC^Cre/+ mice fed the HFpEF diet was observed. Similarly, glucose and insulin sensitivities were similarly reduced in PGP^+/+ αMHC^Cre/+ and PGP^D34N/D34N αMHC^Cre/+mice on the HFpEF diet. By echocardiographic assessment, we found that HFpEF diet-induced PGP^D34N/D34N αMHC^Cre/+ had worsened left ventricular diastolic posterior and anterior wall thicknesses, as well as increased left ventricular mass, as compared to HFpEF diet-induced PGP^+/+ αMHC^Cre/+. When measuring diastolic function directly, E/e’ ratios in PGP^D34N/D34N αMHC^Cre/+ mice fed the HFpEF diet was also worsened, as compared to PGP^+/+ αMHC^Cre/+ control HFpEF diet fed mice. Molecularly, inhibition of PGP activity in CMs as well as inhibition of PGP in inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) indicate decreased glycolysis and fatty acid oxidation. Finally, inhibition of PGP activity led to increased lipid droplet accumulation in CMs, supporting our hypothesis that loss of PGP activity leads to a worsened cardiac phenotype in response to HFpEF.
Conclusions: Collectively, these data demonstrate that while inhibiting PGP activity in CMs does not affect glucose or insulin tolerance, it worsens diastolic dysfunction, increases cardiac mass, and increases hypertrophy in response to HFpEF diet. Taken together, these data suggest that PGP is an essential regulatory enzyme important in protecting the heart in response to cardiac stress responses such as HFpEF.