Cardiac-Specific Overexpression of Transcription Factor JunD Leads to Enlarged Infarct

Introduction:
Myocardial injury during short-term ischemia (I) and reperfusion (R) has become clinically important with the use of primary PCI as a first-line strategy in patients with acute coronary syndrome (ACS). The Jun family of activator protein 1 (AP-1) transcription factors (c-Jun, JunB, JunD) is involved in fundamental biological processes such as proliferation, apoptosis, tumor angiogenesis, and hypertrophy. Its member junD is specifically expressed in the developing heart and cardiovascular system. Current evidence suggests a complex role for junD in the adult heart. However, there is little in vivo evidence about how exactly junD acts in the myocardium. In the present study we analyzed the role of junD in the heart using cardiac-specific junD transgenic mouse line (cJunDTG) subjected to I/R.

Methods:
8-12-week-old cJunDTG males and corresponding C57Bl/6 wild-type (WT) controls were subjected to 30 min of I followed by 24h of R. Infarct size was assessed morphologically.

Results:
After I, cJunDTG mice developed markedly larger infarcts as compared to WT. This was further associated with increased post-ischemic levels of serum cardiac troponin I. However, the observed effect on infarct size was not due to initial impaired contractility of transgenic hearts as confirmed by MRI. Capillary density observed in transgenic hearts after I/R was significantly decreased compared to WT as assessed by CD31 and smooth muscle actin staining of heart cross sections. Finally, both messenger RNA and protein levels of Vascular Endothelial Growth Factor A (VEGF-A) were impaired in infarcted transgenic hearts compared to corresponding controls.

Conclusions:
Thus, junD promotes increased sensitivity to I/R when expressed at unphysiological levels in the mouse heart. Such junD-associated cardiac phenotype seems to be driven by the impaired angiogenesis. Therefore, junD might represent a potential therapeutic target to protect human heart from myocardial infarct in future.