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.