Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

Abstract

BackgroundThere is evidence for inflammation, autophagy, and apoptosis in the ischemic heart. Autophagy is a physiologic process for tissue survival. Apoptosis, on the other hand, is a mechanism that serves to clear the debris in the setting of tissue injury. The balance between autophagy and apoptosis may be important in cell survival and cardiac function.Methods and ResultsWe examined the interplay of inflammation and myocyte autophagy and apoptosis during the ischemic process. We subjected mice to total left coronary artery ligation and studied these animals for up to 4 weeks. The inflammatory (tumor necrosis factor [TNF]‐α, monocyte chemoattractant protein‐1, interleukin‐6, and interleukin‐1β) and autophagic signals (light chain‐3 and beclin‐1) were strongest during the first week and then began to decline. However, the apoptotic signals peaked at week 2 after left coronary artery ligation, and the elevated levels persisted until the end of the fourth week. To elucidate the role of inflammation in the regulation of myocyte autophagy and apoptosis, we administered TNF‐α inhibitor (CAS1049741‐03‐8, Millipore, Burlington, MA) to the mice daily during the first week of myocardial infarction. Anti‐TNF‐α therapy reduced the levels of inflammatory cytokines and the inflammatory cell infiltration in and around the infarct area. However, cardiac function measured by echocardiography (fractional shortening and ejection fraction) worsened with anti‐TNF‐α therapy. More importantly, application of TNF‐α inhibitor markedly inhibited autophagy and promoted myocyte apoptosis in the border zone.ConclusionsThese observations suggest that inflammatory response may be protective in the early stage of the myocardial infarction through stimulation of myocyte autophagy. Anti‐inflammatory treatment early after coronary occlusion may have an adverse effect.

Complexity of TNF-α Signaling in Heart Disease

“…Moreover, a single dose of etanercept injected at the time of myocardial infarction improved long-term cardiac function and reduced cardiac tissue remodeling in rats [ 107 ]. In another study, pharmacological inhibitor preventing TNF-α binding to its receptor (CAS1049741-03-8) reduced post-infarction inflammatory response but worsened cardiac function due to enhanced cardiomyocyte apoptosis [ 108 ]. The injection of anti-TNF-α antibody 3 h prior to ischemia–reperfusion was also shown to reduce endothelial dysfunction by reducing the production of endothelial ROS [ 109 ].…”

Programmed Cell Death in the Left and Right Ventricle of the Late Phase of Post-Infarction Heart Failure

“…However, it should be mentioned that such cooperation cannot be ruled out in other settings. Indeed, it might have taken place earlier into reperfusion, as a gradual decline in autophagic activity following its primary rise as a reaction to acute myocardial damage shortly after MI was reported in a study by Wang et al [ 6 ]. This might explain the lack of autophagy but increased pro-necroptotic environment in the LV of failing hearts 6 weeks after MI.…”

“…Understanding the mechanisms of cell death in heart failure (HF) after myocardial infarction (MI) is of great clinical importance, since the extent of cellular loss significantly determines the degree of cardiac injury, contractile dysfunction, adverse remodeling and finally patient prognosis [ 1 , 2 , 3 ]. Therefore, an enormous effort has been undertaken to elucidate the role of certain cell death modalities in HF, and current knowledge on autophagy [ 4 , 5 , 6 ] and necroptosis [ 4 , 7 , 8 , 9 , 10 ], commonly occurring in post-infarction HF [ 4 , 5 , 7 , 8 , 9 , 10 ], has been advanced.…”

Modified Taohong Siwu Decoction Improved Heart Function After Myocardial Infarction by Inhibiting Inflammatory Factor and Promoting Chemotactic and Pro-Angiogenic Factors

“…It has been proposed that in ammation may have protective or detrimental effects on heart function with the progression of myocardial ischemia [33]. For example, although TNF-α was excessively elevated and contributed to cell apoptosis and cardiac dysfunction after myocardial ischemia-reperfusion, the application of TNF-α inhibitor markedly promoted myocyte apoptosis and reduced cardiac function after MI [34]. Therefore, the exact effect of TNF-α during the progression of myocardial ischemia should be further clari ed through more investigations.…”