Ischemic coronary artery disease and cardiomyopathy are diseases that are common and deadly. Morbidity and mortality in patients with heart disease is determined in part by the presence or absence of cardioprotective mechanisms. Myoglobin is a unique hemoprotein. To date there is no evidence of a redundant protein or set of cardioprotective mechanisms that are functional substitutes for myoglobin. Using a gene knockout strategy, we observe that a majority of mice that lack myoglobin display embryonic lethality and have evidence of congestive heart failure and vascular insufficiency. A minority of the myoglobin null progeny is viable, fertile and has preserved cardiac performance under ambient conditions. These surviving myoglobin mutant mice have a marked induction of hypoxia inducible gene expression, increased myocardial vascularization and upregulation of a novel hemoprotein, neuroglobin. The unifying or principle hypothesis of this proposal is that myoglobin is a bifunctional hemoprotein that facilitates oxygen flux and regulates nitric oxide in the cardiomyocyte. In the absence of myoglobin, survival is mediated by established and currently unidentified cardioprotective mechanisms. In this proposal, we plan to gain a more detailed understanding of the molecular and cellular adaptations in the surviving myoglobin null populations. To accomplish our goals we will pursue the following three specific aims: 1) To define specific molecular adaptations that are necessary and sufficient to promote viability in the absence of myoglobin; 2) To define functional role(s) for myoglobin using isolated wild type and myoglobin mutant cardiomyocytes under ambient and stimulated conditions; 3) To define the molecular basis for survival and cardiac performance under extreme environmental conditions in the adult myoglobin deficient mice. The experimental plans take maximum advantage of emerging technologies and powerful model systems. The experiments we propose are hypothesis-driven and focused. The results of this analysis, using unique transgenic mouse models, will enhance efforts to identify novel cardioprotective mechanisms for clinical application to patients with ischemic coronary artery disease or cardiomyopathy.
| Singh, Sarvjeet; Manda, Shilpa M; Sikder, Devanjan et al. (2009) Calcineurin activates cytoglobin transcription in hypoxic myocytes. J Biol Chem 284:10409-21 |
| Kanatous, Shane B; Mammen, Pradeep P A; Rosenberg, Paul B et al. (2009) Hypoxia reprograms calcium signaling and regulates myoglobin expression. Am J Physiol Cell Physiol 296:C393-402 |
| Mammen, Pradeep P A; Shelton, John M; Ye, Qiu et al. (2006) Cytoglobin is a stress-responsive hemoprotein expressed in the developing and adult brain. J Histochem Cytochem 54:1349-61 |
| Garry, Daniel J; Kanatous, Shane B; Mammen, Pradeep P A (2003) Emerging roles for myoglobin in the heart. Trends Cardiovasc Med 13:111-6 |
| Mammen, Pradeep P A; Kanatous, Shane B; Yuhanna, Ivan S et al. (2003) Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice. Am J Physiol Heart Circ Physiol 285:H2132-41 |
