Endothelial dysfunction is an underlying molecular mechanism in ischemia-reperfusion injury of the heart, and has been shown to affect infarct size in myocardial infarction. Myocardial infarction and other coronary heart disease are major health problem that especially affects millions of older people in the United States alone. This damage occurs in part in response to endothelial dysfunction caused by oxidative stress, which increases when blood vessels reperfused ischemic heart tissue. Thus, agents that modulate the redox environment of the heart are potentially useful for treating coronary heart disease. For this reason, our laboratory has been characterizing thioredoxin (Trx), an endogenous enzyme that can reduce oxidative stress and regenerate proteins that have been inactivated by oxidation. In conjunction with this research, we developed two transgenic mouse lines that have altered Trx activity: one (Trx-Tg) overexpresses the protein, whereas the other (dnTrx-Tg) expresses an inactive Trx and thus acts as a conditional Trx knockout. As we characterized these unique mice, we discovered that aged TrxTg mice are protected against myocardial infarction in response to ischemia- reperfusion (I/R), whereas those deficient in Trx, like wild type, undergo extensive myocardial damage. Thus, we hypothesize that increased levels of Trx activity can afford protection against endothelial dysfunction. This hypothesis leads to the Specific Aims of this proposal:
Aim 1 will establish the role of Trx in endothelial dysfunction arising from I/R injury;
Aim 2 will explore potential mechanisms of these effects;
and Aim 3 will determine whether Trx increases the expression of mitochondrial superoxide dismutase as a contributor to protection against endothelial dysfunction. The outcomes of this project will contribute to our understanding of endothelial cell dysfunction in cardiovascular diseases such as atherosclerosis, and propel the development of Trx as a real novel therapeutic approach to treat cardiovascular disease as exogenously added Trx is avidly taken up by endothelial cells.
Coronary heart disease (CHD) remains a major cause of morbidity and mortality in aged American population (AHA 2006. For example, only 0.14% population under the age of 39 was diagnosed with CHD, whereas a staggering 55% of populations over the age of 40 were diagnosed with CHD. Studies proposed in this application will investigate the role of thioredoxin, an endogenous small protein in protecting against myocardial infarction using a transgenic mice model with higher or lower expression of thioredoxin. If successful, these studies will lead into clinical trial of thioredoxin as a therapeutic molecule for treatment of heart in heart failure and other diseases related to obstruction of blood flow.
|Subramani, Jaganathan; Kundumani-Sridharan, Venkatesh; Hilgers, Rob H P et al. (2016) Thioredoxin Uses a GSH-independent Route to Deglutathionylate Endothelial Nitric-oxide Synthase and Protect against Myocardial Infarction. J Biol Chem 291:23374-23389|
|Kundumani-Sridharan, Venkatesh; Subramani, Jaganathan; Das, Kumuda C (2015) Thioredoxin Activates MKK4-NFÎºB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells. J Biol Chem 290:17505-19|
|Das, Kumuda C (2015) Thioredoxin-deficient mice, a novel phenotype sensitive to ambient air and hypersensitive to hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 308:L429-42|
|Hilgers, Rob H P; Das, Kumuda C (2015) Role of in vivo vascular redox in resistance arteries. Hypertension 65:130-9|
|Das, Kumuda C; Wasnick, John D (2014) Biphasic response of checkpoint control proteins in hyperoxia: exposure to lower levels of oxygen induces genome maintenance genes in experimental baboon BPD. Mol Cell Biochem 395:187-98|
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|Das, Kumuda C (2013) Hyperoxia decreases glycolytic capacity, glycolytic reserve and oxidative phosphorylation in MLE-12 cells and inhibits complex I and II function, but not complex IV in isolated mouse lung mitochondria. PLoS One 8:e73358|
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