Fibroblast Senescence: A Risk Factor for Remodeling, Inflammation, and Arrhythmias in the Post‐MI Heart

Abstract

ObjectivesCellular senescence is a stress response involving permanent replicative arrest. It is accompanied by a complex senescence‐associated secretory phenotype (SASP), which is characterized by the presence of pro‐inflammatory cytokines and chemokines, growth factors, and tissue‐remodeling metalloproteinases. Little is known regarding the role of senescence and the SASP in the context of arrhythmias post myocardial infarction (MI). Here, we characterized the arrhythmogenic cardiac consequences and molecular mechanisms underlying tissue remodeling changes in impaired or accelerated cardiac myofibroblast (CMF) senescence and the pro‐inflammatory SASP during post‐MI wound healing process in genetically engineered mice.Material‐MethodsImpaired or accelerated CMF‐specific senescence was achieved by using cre‐lox mouse models to delete p53 or MDM2 genes. MI surgery via direct ligation of the left anterior descending artery (LAD) was performed in 4‐month‐old wild‐type (WT), Pstn‐Cre(+/‐) p53(fl/fl), Pstn‐MerCreMer(+/‐) MDM2(fl/fl), and respective littermate control (LMC) mice of both sexes. Changes in cardiac structure and function post‐MI were assessed by echocardiography. Senescence‐associated β‐galactosidase (SA‐βgal) staining was applied to detect and quantify senescent cells in three zones: infarct zone (IZ), infarct border zone (IBZ), and remote zone (RZ). Immunofluorescence staining identified the types of senescent cells. Masson’s trichrome staining was used for fibrosis assessment. RT‐qPCR was performed to quantitate the expression of known senescence genes and canonical SASP factors.ResultsPstn‐Cre(+/‐) p53(fl/fl) mice displayed significantly decreased CMF senescence two weeks post‐MI in the scar compared to littermate control p53(fl/fl) and WT mice. We noticed a similar trend in the IBZ, but this did not reach statistical significance. Pstn‐MCM(+/‐) MDM2(fl/fl) mice showed significantly increased CMF senescence in the IZ compared littermate control MDM2(fl/fl) mice. We observed a similar trend in the IBZ, but this did not reach statistical significance. In all mice, we observed essentially no senescence in the RZ. Our data did not show any significant difference in fibrosis between any genotype in any zone. We did not observe any overall trend in differential expression in senescence and SASP genes between p53(fl/fl) and Pstn‐Cre(+/‐) p53(fl/fl) mice in any zone. There was no evidence of any sex‐specific differences in aforementioned results.ConclusionsA significant increase and persistence of CMF senescence likely contributes to pathological tissue remodeling during the post‐MI wound healing process. This is likely due to SASP‐induced pro‐arrhythmogenic chronic inflammation or via direct cell‐cell interactions between senescent CMFs and myocytes.