Tissue engineering with targeted delivery of nanotized S-nitrosyl mutant of NEMO ameliorates myocardial infarction.

BACKGROUND

Myocardial infarction (MI) is characterized by an elevated nitrosative and hypoxic microenvironment due to reduced coronary blood flow. NEMO (IKKγ) regulates the formation of the IKK holo-complex to activate NFκB-p65 signaling. This study reports successful restoration of MI through cardiomyocyte-targeted nanotized S-nitrosyl mutant of NEMO under elevated nitrosative stress.

METHODS

The MI model was generated in male Wistar rats. S-nitrosyl mutant of NEMO (R- NEMO) was selectively delivered to the cardiomyocytes via targeted chitosan nano-vehicle.

RESULTS

Nano-conjugated R- NEMO delivery to diseased cardiomyocytes resulted in downregulation of nitrosative stress and cellular apoptosis leading to regressed infarct area with improved cardiac pathophysiology. Mechanistically, NEMO-p300 binding in R- NEMO expressed cells destabilized p65-p300 complex leading to regressed nitrosative stress and cellular apoptosis. The NEMO mutant inhibits the PGC1α-p65 complex-mediated degradation of PGC1α, leading to upregulation of VEGF. A shift in the binding preference of p65 from PGC1α/p300 to HDAC1 results in the downregulation of the cell-cycle inhibitor and the induction of cell-cycle re-entry markers during MI.

CONCLUSION

Tissue-targeted R- NEMO nanoconjugates show potential to ameliorate MI insult by downregulating apoptosis and promoting the proliferative prowess of the resident cardiomyocytes with potential revascularization at infarct sites; thus, repairing the damaged myocardium.