Abstract 13816: Clearing P16+ Cells Prevents Cardiac Dysfunction and Death in Mice With Acute Myocardial Infarction

Abstract

Introduction: Cellular senescence, a stress and age-related response, is often characterized by p16 expression in p16 positive (p16 + ) senescent cells. Senescent cells secrete profibrotic and proinflammatory factors as parts of a “senescence associated secretory phenotype”. The role of cellular senescence in myocardial infarction (MI) is unclear. Aims: To study the effect of p16 + cell clearance on survival, cardiac remodeling and function after MI. Methods: We used INK ATTAC transgenic mice, in which p16 + cells undergo targeted apoptosis upon exposure to a dimerizer, AP20187 (AP). MI mice were treated with AP or vehicle (V), twice a week for 1 month, beginning 3-4 hours post-MI. Cardiac function and structure were evaluated with echocardiography, hemodynamic parameters with a Millar catheter, infarct area with Masson’s Trichrome, gene expression with qPCR and single-nucleus RNA-sequencing (snRNAseq). Results: Survival post MI was dramatically increased in MI-AP vs MI-V mice (P<0.001, Fig A), primarily via prevention of cardiac rupture (CardRup). Left ventricular (LV) ejection fraction (EF%) and LV anterior wall thickness at end diastole (LVAWd) decreased in MI-V vs Sham and improved in MI-AP mice (Fig B), indicating preservation of cardiac function and structure with p16 + cell clearance. Hemodynamic indices of LV function (max and min dP/dt) improved with AP (Fig C). Fibrosis-related gene expression (Col1a1, Col3a1 and Lox; Fig D) increased with MI and improved with AP, paralleling changes in infarct size (Fig E). snRNAseq showed that genes were principally upregulated in MI-V macrophages and neutrophils; significant responses were seen in TNF-α, inflammatory response pathways and gene programs associated with CardRup (Fig F). Conclusion: These results suggest that p16 + cells play a significant role in the evolution of MI, apparently by modulating inflammatory signaling, pointing to an important pathophysiological role of cellular senescence.