CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Unmethylated CpG oligodeoxynucleotide (CpG‐ODN), a Toll‐like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG‐ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG‐ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG‐ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI. Both 1826‐CpG and KSK‐CpG preconditioning significantly improved the left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) when compared with non‐CpG controls. Histological analysis further confirmed the cardioprotection of CpG‐ODN preconditioning. In vitro studies further demonstrated that CpG‐ODN preconditioning increases cardiomyocyte survival under hypoxic/ischemic conditions by enhancing stress tolerance through TLR9‐mediated inhibition of the SERCA2/ATP and activation of AMPK pathways. Moreover, CpG‐ODN preconditioning significantly increased angiogenesis in the infarcted myocardium compared with non‐CpG. However, persistent TLR9 activation mediated by lentiviral infection failed to improve cardiac function after MI. Although CpG‐ODN preconditioning increased angiogenesis in vitro, both the persistent stimulation of CpG‐ODN and stable overexpression of TLR9 suppressed the tube formation of cardiac microvascular endothelial cells. CpG‐ODN preconditioning significantly protects cardiac function against MI by suppressing the energy metabolism of cardiomyocytes and promoting angiogenesis. Our data also indicate that CpG‐ODN preconditioning may be useful in MI therapy.