The broad, long-term objectives of the proposed research are twofold: 1) to further our understanding of the mechanisms underlying the pathophysiology of myocardial ischemia, and; 2) to design rationale therapeutic regimens which will minimize ischemic damage to the heart. The experiments described in this proposal are directed at the beneficial effects of adenosine and pyruvate in the survival and functional improvement of the ischemic and post-ischemic myocardium. Adenosine and pyruvate are attractive candidates for cardioprotection clinically because: 1) their proposed mechanism of action would benefit the heart both during ischemia and reperfusion. and; 2) as rapidly metabolized endogenous compounds their side effects would be minimal.
The specific aims of the proposed research are to investigate: 1. The mechanism of adenosine and pyruvate mediated cardioprotection during ischemia. The in vitro isolated perfused rat heart will be used to determine the effect of adenosine and pyruvate on: a. glycolytic flux during ischemia. b. intracellular calcium levels during and after ischemia. c. cytosolic phosphorylation potential during and after ischemia. 2. The applicability of adenosine and pyruvate as cardioprotective agents in vivo. The effect of cardioprotective doses of adenosine and pyruvate on ventricular function (systolic wall thickening, coronary blood flow, cardiac output, left ventricular dP/dt) and cytosolic phosphorylation potential will be determined before, during, and after myocardial ischemia in two in vivo clinically relevant models of myocardial ischemia: a. regional ischemia and stunned myocardium. b. global ischemia during cardioplegia-induced cardiac arrest. The proposed experiments, which are of clinical importance and potential_therapeutic relevance for humans with ischemic heart disease, will provide fundamental knowledge and basic insights into the potential use of adenosine and pyruvate to improve cardiac survival and recovery in acute myocardial ischemia and reperfusion during conditions pertinent to cardiac surgery.
| Andres, Allen M; Stotland, Aleksandr; Queliconi, Bruno B et al. (2015) A time to reap, a time to sow: mitophagy and biogenesis in cardiac pathophysiology. J Mol Cell Cardiol 78:62-72 |
| Andres, Allen M; Hernandez, Genaro; Lee, Pamela et al. (2014) Mitophagy is required for acute cardioprotection by simvastatin. Antioxid Redox Signal 21:1960-73 |
| Pepe, Salvatore; Mentzer Jr, Robert M; Gottlieb, Roberta A (2014) Cell-permeable protein therapy for complex I dysfunction. J Bioenerg Biomembr 46:337-45 |
| Mentzer Jr, Robert M; Wider, Joseph; Perry, Cynthia N et al. (2014) Reduction of infarct size by the therapeutic protein TAT-Ndi1 in vivo. J Cardiovasc Pharmacol Ther 19:315-20 |
| Jahania, Salik M; Sengstock, David; Vaitkevicius, Peter et al. (2013) Activation of the homeostatic intracellular repair response during cardiac surgery. J Am Coll Surg 216:719-26; discussion 726-9 |
| Gottlieb, Roberta A; Mentzer Jr, Robert M (2013) Autophagy: an affair of the heart. Heart Fail Rev 18:575-84 |
| Giricz, Zoltan; Mentzer Jr, Robert M; Gottlieb, Roberta A (2012) Autophagy, myocardial protection, and the metabolic syndrome. J Cardiovasc Pharmacol 60:125-32 |
| Gottlieb, Roberta A; Gustafsson, Asa B (2011) Mitochondrial turnover in the heart. Biochim Biophys Acta 1813:1295-301 |
| Gottlieb, Roberta A (2011) Cell death pathways in acute ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther 16:233-8 |
| Huang, Chengqun; Liu, Wayne; Perry, Cynthia N et al. (2010) Autophagy and protein kinase C are required for cardioprotection by sulfaphenazole. Am J Physiol Heart Circ Physiol 298:H570-9 |
Showing the most recent 10 out of 57 publications
