Abstract
This study tested the hypothesis that cellular prion protein (PrPC) played an essential role in myocardial regeneration and recovery of left ventricular ejection fraction (LVEF) from apical takotsubo cardiomyopathy (TCM) induced by transaortic constriction (TAC). In vitro study was categorized into G1 (H9C2), G2 (H9C2-overexpression-PrPC), G3 (H9C2-overexpression-PrPC + Stelazine/1 uM), and G4 (H9C2 + siRNA-PrPC), respectively. The results showed that the protein expressions of PrPC, cell-stress signaling (p-PI3K/p-Akt/p-m-TOR) and signal transduction pathway for cell proliferation/division (RAS/c-RAF/p-MEK/p-ERK1/2) were lowest in G1, highest in G2, significantly higher in G3 than in G4 (all p < 0.001). Adult-male B6 mice (n = 30) were equally categorized in group 1 (sham-control), group 2 (TAC) for 14 days, then relieved the knot and administered BrdU (50 ug/kg/intravenously/q.6.h for two times from day-14 after TAC) and group 3 (TAC + Stelazine/20 mg/kg/day since day 7 after TAC up to day 21 + BrdU administered as group 2), and animals were euthanized at day 28. The results showed that by day 28, the LVEF was significantly higher in group 1 than in groups 2/3 and significantly higher in group 3 than in group 2, whereas the LV chamber size exhibited an opposite pattern of LVEF (all p < 0.0001). The protein expressions of PrPC/p-PI3K/p-Akt/p-m-TOR/cyclin D/cyclin E and cellular-proliferation biomarkers (Ki67/PCNA/BrdU) exhibited an opposite pattern of LVEF (all p < 0.0001) among the three groups, whereas the protein expressions of RAS/c-RAF/p-MEK/p-ERK1/2 were significantly and progressively increased from groups 1 to 3 (all p < 0.0001). In conclusion, PrPC participated in regulating the intrinsic response of cell-stress signaling and myocardial regeneration but did not offer significant benefit on recovery of the heart function in the setting of TCM.
Highlights
Apical ballooning syndrome, known as takotsubo cardiomyopathy (TCM), apical ballooning cardiomyopathy, stress-induced cardiomyopathy, or stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the myocardium [1,2,3]
This study, which investigated the role of PrPC in myocardial regeneration and recovery of left ventricular function from transaortic constriction (TAC)-induced TCM, yielded several preclinically striking implications
A rebound/feedback phenomenon, i.e., more markedly upregulated cell proliferation/survival biomarkers (RAS, c-RAF, p- MEK, and p-ERK1/2), due to the cell-stress signaling blocked by Stelazine was distinctively observed in the in vivo study
Summary
Known as takotsubo cardiomyopathy (TCM), apical ballooning cardiomyopathy, stress-induced cardiomyopathy, or stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the myocardium [1,2,3]. A recent study has keenly investigated hyperglycemia attenuated anticancer effects and augmented its cardiotoxicity in cellular models through mechanisms of regulating NLRP3 inflammasome and MyD88 signaling [25], suggesting hyperglycemia increased cytokine storm in human cancer cells and cardiotoxic induced by anticancer therapies [25]. These findings may raise consideration of the correlation between PrPC and NLRP3 inflammasome and its role in cardiac dysfunctions induced by TCM. Using in vitro and in vivo studies, we tested the hypothesis that PrPC may participate in the regeneration of damaged myocardium and recover LV function in the setting of TCM
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