MEK1‐induced physiological hypertrophy inhibits chronic post‐myocardial infarction remodeling in mice

Abstract

Although activation of MEK-ERK signaling is known to be cardioprotective during acute reperfusion injury, the effect of MEK activation on chronic changes in ventricular structure and function during the more complex process of remodeling after myocardial infarction (MI) with or without reperfusion remains uncertain. Four weeks after permanent coronary ligation, LV fractional shorting, preload recruitable stroke work, and end-systolic elastance were all preserved in transgenic mice with CM-specific upregulation of the MEK1-ERK1/2 signaling pathway (MEK1 Tg) compared to wildtype (WT) controls (5.8% decline vs. 17.3%, P < 0.01; 603 ± 98 mmHg vs. 335 ± 98, P < 0.05; 6.14 ± 0.57 mmHg/µl vs. 3.92 ± 0.60, P < 0.05, respectively). Despite similar initial infarct sizes, post-MI remodeling was significantly reduced in MEK1 Tg, demonstrated by reductions in chronic infarct size (28.5 ± 3.1% vs. 47.8 ± 3.2%), myocardial fibrosis (3.98 ± 0.74% vs. 9.27 ± 1.97%) and apoptosis (0.66 ± 0.11% vs. 1.60 ± 0.34%). Higher phosphorylation (i.e., activation) of pro-survival transcription factor STAT3, higher expression of anti-apoptotic protein Bcl2, and higher phosphorylation (i.e., inactivation) of pro-apoptotic BAD were observed in the post-MI remote myocardium of MEK1 Tg. MMP2 activity was higher in MEK1 Tg, while expression of TIMP3 and MMP9 activity were lower in transgenic mice. Beyond any immediate cardioprotective effect, therapeutic activation of MEK1-ERK1/2 signaling during the chronic post-MI period may preserve LV function by increasing the expression of pro-survival factors and by suppressing factors, such as the balance between matrix modulating proteins, that promote pathological remodeling in the remote myocardium.

Circulating Matrix Metalloproteinase-2 and -9 Enzyme Activities in the Children with Ventricular Septal Defect

“…Our published paper proposed that the interaction between MMP-2, MMP-9 and TIMP-3 may contribute to atrial ECM remodeling of atrial fibrillation 19. In addition, many studies also appear that the association of MMP-2, MMP-9 and TIMP-3 in heart diseases 31, heart remodeling 32, 33 and cardiocytes function properly 34, and supported that MMP-2, MMP-9 and TIMP-3 may play important role in VSD.…”

Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction

“…Previous studies have shown that melusin enhances Erk1/2 signalling 4,5 , a pathway well known for its protective function after MI 13 . As shown in Figure 2C, Erk phosphorylation in cardiomyocytes at 3 days after MI was maximal in the border zone as detected by both phospho-Erk staining intensity and percentage of positive nuclei.…”

Spacial and Temporal Patterns of Gene Expression After Cardiac MEK1 Gene Transfer Improve Post‐Infarction Remodeling Without Inducing Global Hypertrophy

“…All mice underwent left thoracotomy after intubation and mechanical ventilation. The left anterior descending artery (LAD) was ligated with 7.0 polypropylene suture as described previously [Yeh et al, 2010[Yeh et al, , 2013. In some animals, 100 mL of saline containing 10 11 genome copies (GC) of either AAV or vehicle were injected into the left ventricular chamber approximately 5 min prior to LAD ligation.…”

“…Transthoracic echocardiography was performed in conscious mice using an Acuson Sequoia 512 machine and a 13-MHz probe [Yeh et al, 2010[Yeh et al, , 2013. A two dimensional short-axis view of the left ventricle was obtained at the level of the papillary muscles, that is, in myocardium remote to the infarction, and two-dimensional M-mode tracings were also recorded.…”

“…In fact, it has been hypothesized that the diversion between physiologic hypertrophy versus pathologic hypertrophy may depend on the balance between MEK1-ERK1/2 signaling and the activity of p38 and JNK pathways within cardiac myocytes. Our group has previously pursued validation of a therapeutic strategy based on this hypothesis, and, in a transgenic model of constitutive MEK1 activation, has demonstrated that cardiac myocyte-specific upregulation of MEK1-ERK1/2 signaling improves chronic post-MI remodeling and preserves ventricular function [Yeh et al, 2013].…”