The Role of Myofibroblast Senescence in Arrhythmogenesis of the Aged Infarcted Heart

• DOI: 10.1096/fasebj.2018.32.1_supplement.717.13
• Publication Date: 2021-06-21T16:28:03Z
• Authors: Brett Christopher...; Kevin Murphy; Yueming Cao; Nilufer Turan; Yichun Lu; John Sedivy; Gideon Koren
• Keywords: Senescence; Myofibroblast; Ventricular remodeling; Cardiac Fibrosis

Aging is associated with a more than 5‐ to 40‐fold increase in the incidence of sudden cardiac death. Our laboratory has established female New Zealand White rabbit as model aging heart, young (5–9 months) and old (4–6 years) rabbits recapitulate human pathophysiology. Previously we developed minimally invasive procedure involving coil embolization left coronary artery reproducibly induce myocardial infarction (MI) 25–35% ventricular free wall (Morrissey 2017). Aged experience increased periprocedural fibrillation, electrophysiological remodeling, that survive MI, an death comparable pathology MI aged humans. Cellular senescence, cell cycle arrest process, critically important for wound healing many tissues including heart. Senescence myofibroblasts (CMFs) short‐term limits fibrosis scar formation improves function post‐MI (Zhu 2013). In liver epidermis, detrimental long‐term persistence senescent cells which promotes chronic inflammation, but changes CMF senescence physiological consequences heart remain elusive. We hypothesized response age these contribute arrhythmogenic observed To test this, infarcted after three weeks, performed histological biochemical assays on rapidly frozen tissue sections. used senescence‐associated beta galactosidase (SA‐βGal) staining characterize zone, infarct border zone (IBZ), remote (RZ). Compared rabbits, CMFs weeks post‐MI. investigate temporal dynamics measured via SA‐βGal across three‐week time course. The results showed delayed persistent Additionally, probe gene expression qPCR measure genes involved regulation well secretory phenotype (SASP) from scar, IBZ, RZ. SASP factors include pro‐inflammatory cytokines matrix remodeling proteins, correlate age‐associated inflammation. significant particularly zone. data demonstrate onset magnitude propose lead inflammation facilitates arrhythmias around Therefore, limiting may be novel target reduce lethal arrhythmogenesis preserve Support or Funding Information This dissertation based upon work supported by NIH grants R01‐HL110791 (to G. Koren), R21‐AG049608 J. Sedivy T32AG041688 Sedivy). abstract Experimental Biology 2018 Meeting. There no full text article this published FASEB Journal .