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

Abstract

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.

Complex II ambiguities—FADH2 in the electron transfer system

“…( 264 ) is similar or identical to zooms into 33 figures from ref. ( 49 , 57 , 70 , 72 , 133 , 154 , 186 , 244 , 246 , 249 , 251 , 252 , 253 , 254 , 255 , 257 , 262 , 263 , 264 , 267 , 269 , 270 , 272 , 273 , 275 , 276 , 277 , 278 , 279 , 280 , 317 , 319 ). H , the CII ambiguity in FADH 2 →FAD+2H + ( 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , ...…”

DJ-1 interacts with the ectopic ATP-synthase in endothelial cells during acute ischemia and reperfusion

“…It is widely accepted that protein DJ-1 is implicated in cell survival following I/R and oxidative stress, as previously proven both in vitro and in vivo by loss-of-function models of myocardial infarction and stroke 34 , 41 – 47 . However, although many molecular functions have been attributed to DJ-1, there is not yet a consensus on its exact molecular function.…”

“…Whilst ischemia represents a profound detrimental factor, with no other resolution than reperfusion, the rapid recovery of basal conditions paradoxically carries the potential to exacerbate damage itself in a process tightly correlated to the duration and severity of the ischemic insult 58 . Thus, despite being ischemia the most detrimental factor, the cell response to reperfusion directly impacts on the extent of damage 47 In the context of ischemia and I/R, Akt has a number of positives effects as is the case of the inhibition of apoptosis and the promotion of angiogenesis 36 – 38 . Several reports have shown an activation of Akt during early reperfusion after ischemia 59 .…”

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

“…In a pig model of IRI with or without ischemic PostC, mitochondrial proteome analysis revealed a dual role for ischemic PostC promoting metabolic reprogramming of the myocardium and a protective response mediated by the voltage-dependent anion channel 2 and DJ-1 in the mitochondria ( Gallinat et al, 2022 ). Cardiac mitochondria are dynamic organelles and organize into differentiated populations.…”