Figure 2: Common Signaling Pathways of Necrosis, Apoptosis, Autophagy, and Inflammation during Acute MI. Under ischemic conditions, a transition from aerobic metabolism to anaerobic metabolism induces acidosis and depletion of ATP levels. The Na+H+ exchanger removes excess H+ out of the cell and Na+ into the cell. Excess Na+ is removed via the Na+/ Ca2+exchanger causing increases in intracellular Ca2+and opening of the MPTP. Cyclosporine has been shown to reduce infarct size through inhibition of MPTP opening. Mitochondria release intrinsic pro-apoptotic mediators (BAX, BNIP3, and cytochrome c) and decrease the release of anti-apoptotic proteins (Bcl-2) to increase apoptosis and necrosis. Activation of apoptosis mediated by the extrinsic pathway in CMs is through TNF-α induction of iNOS and elevated levels of NO. TNF-α decreases antioxidant defenses causing an increase in ROS. Depletion of ATP levels increases the ratio of AMP/ ATP resulting in the activation of AMPK and inhibition of mTOR to activate autophagy. BNIP3, TNF-α-induced rise in intracellular Ca2+through disruption of the sarcoplasmic reticulum (SR), opening of the MPTP, and increased ROS levels also induce autophagy. Rapamycin and everolimus induce autophagy through interaction with mTOR. TNF-α induces NF-κB translocation and the subsequent upregulation of more TNF-α and IL-6. IL-6 induces expression of ICAM-1 in CMs and targets these cells for neutrophil-mediated cell death.