In the US there are ~750,000 heart attacks (acute myocardial infarctions) a year, and ~300,000 patients undergo scheduled cardiac ischemia during cardiac surgery. Beyond reperfusion itself, there are no FDA- approved interventions to limit myocardial injury due to ischemia and reperfusion (IR). This renewal proposal is part of an ongoing program to elucidate mitochondrial & metabolic events in IR and exploit this knowledge to develop small molecule cardioprotective therapies. Our focus is the interplay between acid pH and metabolism in the ischemic heart, based on the following discoveries: (i) SIRT1 is required for cardioprotection and protective metabolic remodeling. (ii) Among the metabolites regulated by SIRT1 is 2- hydroxyglutarate (2-HG), a hypoxic signaling molecule. (iii) We have found a novel mechanism by which SIRT1 can affect metabolism - impacting cardiomyocyte pH via signaling to NHE1. (iv) Acidosis in ischemia is cardioprotective, but the mechanisms are poorly defined. We have discovered key metabolic events in ischemia are triggered by direct effects of acid on metabolic enzymes. (v) We propose 2-HG activates Hypoxia Inducible Factor (HIF) and inhibits the necrosis mediator Alk-B homolog 7 (ALKBH7). (vi) It is thought that reversal of mitochondrial complex II (Cx-II) drives accumulation of succinate, which then drives pathologic ROS generation at reperfusion. However, new data suggest poor consensus on the mechanism of succinate accumulation, its possible roles in ischemia, and its regulation by pH. Overall, we hypothesize that SIRT1 enhances ischemic acidosis, triggering cardioprotective metabolic events including 2-HG and succinate accumulation. This hypothesis will be tested through pursuit of the following specific aims? Aim 1 will investigate the mechanism by which SIRT1 enhances ischemic acidosis.
Aim 2 will investigate mechanisms by which acid and 2-HG signal cardioprotection.
Aim 3 will investigate the mechanism(s) of ischemic succinate accumulation and the timing of Cx-II inhibition for therapeutic benefit. These studies will use adult cardiomyocytes, perfused hearts, the in-vivo LAD occlusion model of IR injury, and engineered mice including Alkbh7-/- and cardiac specific Sirt1-/-. We will also employ novel pharmacologic agents (Cx-II inhibitors and cell-permeable 2-HG analogs), fluorescent pH imaging, LC-MS/MS based metabolomics, and 13C dynamic labeling metabolomics. This work will advance fundamental knowledge on ischemic cardiac metabolism, will develop small molecule therapies, and will offer mechanistic insight applicable to multiple tissues and pathologies.
Heart attack (myocardial infarction) is a major killer in western society, so there is a drastic need for therapies to avoid myocardial injury. The heart is a very metabolically demanding organ, but there are still large gaps in our knowledge of cardiac metabolism. We have identified a number of key metabolic events that take place during and after heart attack, and this project will investigate how manipulating these events with small molecule drugs can impact the outcome of heart attack.
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|Sahni, Prateek V; Zhang, Jimmy; Sosunov, Sergey et al. (2018) Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice. Pediatr Res 83:491-497|
|Smith, Charles Owen; Nehrke, Keith; Brookes, Paul S (2017) The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection. Biochem J 474:2067-2094|
|Brookes, Paul S; Taegtmeyer, Heinrich (2017) Metabolism: A Direct Link Between Cardiac Structure and Function. Circulation 136:2158-2161|
|Nadtochiy, Sergiy M; Wang, Yves T; Zhang, Jimmy et al. (2017) Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation. Biochem J 474:2829-2839|
|Wang, Hezhen; Huwaimel, Bader; Verma, Kshitij et al. (2017) Synthesis and Antineoplastic Evaluation of Mitochondrial Complex?II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin?A5. ChemMedChem 12:1033-1044|
|Resseguie, Emily A; Brookes, Paul S; O'Reilly, Michael A (2017) SMG-1 kinase attenuates mitochondrial ROS production but not cell respiration deficits during hyperoxia. Exp Lung Res 43:229-239|
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