Mixture of MMP-2, MLC, and NOS Inhibitors Affects NO Metabolism and Protects Heart from Cardiac I/R Injury

Figure 8

The elements of the cardiac ischemia/reperfusion injury pathway targeted by multidrug therapy with Doxy, L-NAME, and ML-7. Oxidative stress resulting from I/R leads to upregulation of iNOS, eNOS, phospho-eNOS (targeted by L-NAME), and ADMA. ADMA promotes uncoupling of NOS and production of superoxide (O₂^•−). Increased level of NOS-derived NO reacts with O₂^•− forming highly reactive peroxynitrite (ONOO⁻), which limits NO bioavailability. ONOO⁻ activates MMP-2 (activity of MMP-2 was targeted by Doxy) which degrades MLC. Increased phosphorylation of MLC by MLCK (targeted by ML-7) increases its susceptibility to MMP-2 degradation. ADMA, asymmetric dimethylarginine; Doxy, doxycycline; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; L-NAME, inhibitor of NOS; ML-7, inhibitor of MLC phosphorylation; MLC, myosin light chain; MLC-phos, phosphorylated myosin light chain; MLCK, myosin light chain kinase; MMP-2, matrix metalloproteinase-2; NO, nitric oxide; phopho-eNOS, phosphorylated (S1177) eNOS.