Cardiac ischemia-reperfusion (IR) injury is the pathologic process underlying heart-attack (acute myocardial infarction, AMI). Despite decades of research, cardioprotective therapies are scant, and AMI kills >220,000 people annually in the US. In addition, >380,000 patients/yr. undergo predictable ischemia during cardiac surgery. The overall goal of this ongoing program is to develop new cardioprotective therapies for IR injury. This is a competing renewal application, and in the previous funding cycle we published 19 primary research articles directly attributable to this award (and 17 additional papers). During this time we identified two key signaling players in the endogenous cardioprotective phenomenon of acute ischemic preconditioning (IPC). First, we showed NO?derived nitro-lipids is generated in IPC, and covalently adducts mitochondrial adenine nucleotide translocase 1 (ANT1). This causes mild uncoupling of mitochondrial oxidative phosphorylation, which is independently known to protect against IR injury. Second, we showed that the lysine deacetylase SIRT1 is necessary for acute cardioprotective signaling, and that SIRT1 transgenic mice are endogenously protected against IR injury. While these mechanisms may initially appear distinct, our preliminary data show that nitro-lipids covalently modify SIRT1, suggesting cross-talk between nitro-lipid &SIRT1 signaling. The downstream mechanisms which mediate cardioprotection by nitro-lipids and SIRT1 are poorly defined, but our preliminary data suggest the importance of alterations in metabolism and the stimulation of mitophagy, both of which are implicated in cardioprotection. Furthermore, we have developed a cell-based screening platform applicable to adult primary cardiomycytes, enabling discovery of small molecules which can engage these mechanisms to protect the heart from IR injury in-vivo. Overall, these observations have led to the central hypothesis that nitro-lipids &SIRT1 act in concert to protect the heart from IR injury via alterations in metabolism and mitophagy. In this project, we will exploit these endogenous protective pathways for therapeutic benefit, by delivering small molecules that modulate them both prior to ischemia AND at reperfusion. The end goal is to deliver novel cardioprotective molecules for pre-clinical development. To achieve this goal and test our hypothesis, we will pursue three following specific aims:
Aim 1 will identify cardioprotective targets of nitro-lipid action, with a focus on ANT1 and mitophagy.
Aim 2 will investigate cardioprotective targets of SIRT1, with a focus on metabolism.
Aim 3 will develop screening hits, with a focus on molecules that impact mitophagy and metabolism. Addressing these aims will yield a series of small molecule candidates for pre-clinical development as cardioprotective therapeutics, and will enhance our understanding of the underlying mechanisms of cardioprotection.
During a heart attack, blockage of a coronary artery starves the cardiac tissue of oxygen and nutrients, a condition termed ischemia. The goal of this project is to develop new drugs to protect the heart during ischemia. In the previous funding cycle, we identified two key endogenous signals which play a role in cardioprotection, and this new project will find out more about these signals and how they work, as well as exploit these signals to design new therapies. The first signal is a family of lipids termed nitro-lipids, and the second isa protein called SIRT1. We propose that these signals work together, to alter the metabolism of the heart, and to promote endogenous recycling mechanisms inside heart cells. Together this brings about a protected state. We have also developed a screening assay, which allows us to find new small molecules that can trigger these protective signals. Thus, we are in possession of a number of drug candidates, which the project will develop into therapeutics. Every year in the US, over 220,000 people die from a heart attack (acute myocardial infarction) and a further 380,000 undergo a transient ischemic event during cardiac surgery. It is hoped that the small molecules emerging from this project will offer therapeutic benefit to these individuals.
|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|
|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|
|Brookes, Paul S; Taegtmeyer, Heinrich (2017) Metabolism: A Direct Link Between Cardiac Structure and Function. Circulation 136:2158-2161|
|Sahni, Prateek V; Zhang, Jimmy; Sosunov, Sergey et al. (2017) Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice. Pediatr Res :|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Nadtochiy, Sergiy M; Schafer, Xenia; Fu, Dragony et al. (2016) Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling. J Biol Chem 291:20188-97|
|Zhang, Jimmy; Nadtochiy, Sergiy M; Urciuoli, William R et al. (2016) The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy. Am J Physiol Heart Circ Physiol 310:H29-38|
|Pell, Victoria R; Chouchani, Edward T; Murphy, Michael P et al. (2016) Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy. Circ Res 118:898-906|
|Shi, Xi; O'Neill, Margaret M; MacDonnell, Scott et al. (2016) The RSK Inhibitor BIX02565 Limits Cardiac Ischemia/Reperfusion Injury. J Cardiovasc Pharmacol Ther 21:177-86|
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