SERCA inhibition attenuates medial thickening in an organ culture model of coronary artery disease

Atherosclerotic coronary artery disease (CAD) involves de‐differentiation of coronary smooth muscle (CSM) from a quiescent, contractile phenotype to a proliferative, migratory phenotype. We tested the hypothesis that sarco‐endoplasmic reticulum Ca 2+ ATPase (SERCA) function is causal in CSM transition from contractile to proliferative. We measured proliferation with immunohistochemical analysis of Ki‐67 expression in both mild and severe atherosclerotic plaques. Ki‐67 expression peaks early in CAD progression, dropping off in severe CAD, likely because CSM either further differentiate into osteogenic CSM or become apoptotic. We concurrently examined SERCA function with fura‐2 assessment of caffeine‐induced sarcoplasmic reticulum (SR) Ca 2+ store release and subsequent recovery. SERCA function is elevated in mild, early CAD and decreases in more advanced, severe CAD, mirroring Ki‐67 expression patterns. We cultured coronary arterial segments in DMEM with 180 mg/dL glucose and 20% fetal bovine serum for fourteen days, in the presence and absence of the selective SERCA inhibitor, cyclopiazonic acid (CPA). Initial results indicated that CPA treatment completely prevented culture‐induced medial thickening as assessed by histological staining. CSM were enzymatically dispersed and loaded with fura‐2/AM. CPA was absent from the dispersal and experimental solutions. SR Ca 2+ store release and subsequent recovery below baseline levels were increased in CSM from CPA‐treated arteries, suggesting that functional inhibition induces of SERCA expression. We will examine SERCA and Ki‐67 expression in future studies to further examine the role of SERCA in the contractile‐to‐proliferative transition in atherosclerotic CAD. Support or Funding Information NIH HL062552, IUSM CECARE, AHA 15PRE25280001