Network-Assisted Systems Biology Analysis of the Mitochondrial Proteome in a Pre-Clinical Model of Ischemia, Revascularization and Post-Conditioning

Infarct size is the major risk predictor for developing heart failure after an acute myocardial infarction (AMI). The discovery of the conditioning phenomena (i.e., repetitive brief cycles of ischemia applied either before or after a prolonged ischemic insult) has highlighted the existence of endogenous protective mechanisms of the heart potentially limiting infarct size after revascularization. However, most cardioprotective strategies, aiming at infarct size reduction, have failed in clinical studies. Thus, cardioprotection is an unmet clinical need. In the present study, we took a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium after ischemia, ischemia with direct revascularization, and ischemia with re-establishment of blood flow by post-conditioning in a swine model of AMI. Furthermore, network extension with the ENCODE project human regulatory data allowed the prediction of potential transcription factors at play in the response to post-conditioning of the myocardium. Collectively, our results identify cardiac metabolism as a driver of cardioprotection, highlighting a dual role for post-conditioning promoting metabolic reprogramming of the myocardium, and a protective response mediated by VDAC2 and DJ-1 in the mitochondria.

Automated summary

Infarct size is a major risk predictor for heart failure after acute myocardial infarction (AMI). The discovery of conditioning phenomena has revealed the existence of endogenous protective mechanisms that can limit infarct size after revascularization. However, most strategies aiming to reduce infarct size have failed in clinical studies, highlighting the need for cardioprotection. This study used a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium in a swine model of AMI. The results identified cardiac metabolism as a driver of cardioprotection and highlighted the role of post-conditioning in promoting metabolic reprogramming of the myocardium and a protective response mediated by VDAC2 and DJ-1 in the mitochondria.