Distinctive ERK and p38 signaling in remote and infarcted myocardium during post‐MI remodeling in the mouse

Abstract

Global activation of MAP kinases has been reported in both human and experimental heart failure. Chronic remodeling of the surviving ventricular wall after myocardial infarction (MI) involves both myocyte loss and fibrosis; we hypothesized that this cardiomyopathy involves differential shifts in pro- and anti-apoptotic MAP kinase signaling in cardiac myocyte (CM) and non-myocyte. Cardiomyopathy after coronary artery ligation in mice was characterized by echocardiography, ex vivo Langendorff preparation, histologic analysis and measurements of apoptosis. Phosphorylation (activation) of signaling molecules was analyzed by Western blot, ELISA and immunohistochemistry. Post-MI remodeling involved dramatic changes in the phosphorylation of both stress-activated MAP (SAP) kinase p38 as well as ERK, a known mediator of cell survival, but not of SAP kinase JNK or the anti-apoptotic mediator of PI3K, Akt. Phosphorylation of p38 rose early after MI in the infarct, whereas a more gradual rise in the remote myocardium accompanied a rise in apoptosis in that region. In both areas, ERK phosphorylation was lowest early after MI and rose steadily thereafter, though infarct phosphorylation was consistently higher. Immunostaining of p-ERK localized to fibrotic areas populated primarily by non-myocytes, whereas staining of p38 phosphorylation was stronger in areas of progressive CM apoptosis. Relative segregation of CMs and non-myocytes in different regions of the post-MI myocardium revealed signaling patterns that imply cell type-specific changes in pro- and anti-apoptotic MAP kinase signaling. Prevention of myocyte loss and of LV remodeling after MI may therefore require cell type-specific manipulation of p38 and ERK activation.

SIRT1 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the Oxidative Stress and p38MAPK Pathways

“…Oxidative stress has been suggested to cause the activation of p38MAPK, which is the primary target in oxidative stress-induced heart injury [11,20,21]. In the present study, we have demonstrated that SIRT1 can inhibit p38MAPK phosphorylation and protect cardiomyocyte function.…”

Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction

“…ERK and p38 MAPK are the members of MAPK, which are activated by oxidative stress, and both ERK and p38 MAPK also regulate cardiomyocyte hypertrophy during LV remodeling. Yeh and colleagues reported that ERK phosphorylation was increased in mice after 4-week post MI and related with cardiac hypertrophy (Yeh et al 2010). Vildagliptin and combined vildagliptin and metformin reduced ERK phosphorylation, thus attenuating cardiomyocyte hypertrophy in our rat model of obeseinsulin-resistant and normal rats with chronic MI (Fig.…”

Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

“…A study by Li et al (2009) showed an increase in ERK phosphorylation in saline-injected control hearts at 1 week after MI, and this increase was considerably less pronounced in MSC-transplanted hearts. In addition, increased p-ERK1/2 activation was reported in infarcted and remote regions in the post-MI hearts (Yeh et al, 2010a). The study also suggested that the increase in mitogen-activated protein kinase kinase-1/ERK signaling may be predominantly localized in the nonmyocytes in the scar and fibrotic regions.…”