Abstract Body: Introduction: HFpEF is known to associate with multiple comorbidities, such as diabetes hypertension, obesity, and old age.
Aim: To elucidate the role of senescence, we applied a clinically relevant multiple-hit cardiometabolic stress, including 10 months of high-fat diet, low dose streptozocin, L-NAME and middle age (designated as 4-Hit) in p16-3MR mice.
Method/Result: The p-163MR mice express trimodality reporter fusion protein under the control of p16^INK promoter. The 3MR contains Renilla luciferase, red fluorescent protein (RFP reporter), and truncated herpes simplex virus 1 thymidine kinase. Since most senescent cells express p16^INK4a, these p16-3MR mice highlight p16 positive senescent cells that can be ablated by ganciclovir, thus creating a genetic senolytic therapy. After 10 months, these obese, diabetic, and hypertensive middle-aged mice developed LV hypertrophy, with ~50% increase in LV mass, without significant change in ejection fraction, but impaired diastolic function measured by E`/A` and E/E`. The HFpEF was confirmed by a decrease in -dP/dt (Millar), exercise intolerance, and increased lung congestion. Genetic senolytic by 3 cycles of ganciclovir during the final 6 weeks ameliorated the HFpEF phenotypes, in parallel with attenuation of 4-Hit-induced RFP signals, without affecting the body weight or blood glucose. There was increased macrophage infiltration in the heart and kidney of 4-Hit mice, which was prevented by senolytic. Ingenuity Pathway Analysis of cardiac proteomics revealed EIF2, Mitochondrial dysfunction, Sirtuins, FAO, ILK, IL-22 and NRF2 among the top affected pathways. Human iPS-derived cardiomyocytes stressed with palmitate and irradiation demonstrate several transcriptomic signatures of senescence and inflammation, which were attenuated by siRNA of ZBP1 (a sensor of cytosolic DNA in response to DNA damage) or inhibition of cGAS/STING pathway. Interestingly, senolytic also attenuated ZBP1 and cGAS/STING, suggesting a feedback mechanism.
Conclusion: Our study supports a critical role of DNA damage, ZBP1, cGAS/STING and senescence in HFpEF induced by multiple comorbidities.