Fig. 8. Proposed signaling pathway for the Toll-like receptor 4 (TLR4)-mediated cardiac protection against ischemia-reperfusion (I/R). TLR4 activation by its ligand, such as lipopolysaccharide (LPS), leads to inducible nitric oxide synthase (iNOS) induction and increased nitric oxide (NO) production through a myeloid differentiation factor 88 (MyD88)-dependent mechanism. NO protects myocardium via soluble guanylate cyclase (sGC)- and cGMP/protein kinase G (PKG)-dependent mechanisms. 1400W, a potent iNOS inhibitor, blocks LPS/TLR4-induced NO production and inhibits its cardiac protection. In contrast, TIR-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif) is not required for the TLR4-mediated cardiac protection.