التفاصيل البيبلوغرافية
| العنوان: |
Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury. |
| المؤلفون: |
Visker JR, Cluntun AA, Velasco-Silva JN, Eberhardt DR, Shankar TS, Hamouche R, Ling J, Kwak H, Hillas Y, Aist I, Tseliou E, Navankasattusas S, Chaudhuri D, Ducker GS, Drakos SG, Rutter J |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 04. Date of Electronic Publication: 2024 Feb 04. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (Δψ), and Ca 2+ , increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury. |
| التعليقات: |
Update in: JCI Insight. 2024 Jul 25:e180906. doi: 10.1172/jci.insight.180906. (PMID: 39052437) |
| معلومات مُعتمدة: |
K99 HL168312 United States HL NHLBI NIH HHS; R01 GM094232 United States GM NIGMS NIH HHS; T32 DK091317 United States DK NIDDK NIH HHS; T32 HL007576 United States HL NHLBI NIH HHS |
| تواريخ الأحداث: |
Date Created: 20240214 Latest Revision: 20240730 |
| رمز التحديث: |
20240730 |
| مُعرف محوري في PubMed: |
PMC10862804 |
| DOI: |
10.1101/2024.02.01.577463 |
| PMID: |
38352459 |
| قاعدة البيانات: |
MEDLINE |
