Date of Award
Medical Doctor (MD)
Raymond R. Russell
The mitochondrial uncoupling proteins (UCPs) are a recently discovered group of proteins that are present in the inner mitochondrial membrane and mediate a variety of important functions. Involved in transmembrane proton transport, UCPs regulate cellular metabolism as well as prevent reactive oxygen species formation (ROS) and detoxify exogenous ROS. In the heart, these proteins may protect tissue during times of ischemic or metabolic stress. Also activated during metabolic stress is AMP-activated protein kinase (AMPK), which has been shown to provide cardioprotection during ischemia/reperfusion. We hypothesized that AMPK activation plays a role in upregulating the expression of uncoupling proteins UCP2 and UCP3 in the heart. Using both tissue and cellular models, we demonstrate that pharmacologic activation of AMPK with the AMP-analogue, AICAR, leads to increases in UCP2 and UCP3 mRNA and protein expression at both one-hour and twenty-four hour incubation time points. Furthermore, we identify a segment of the UCP3 promoter that can mediate AMPK-activated transcription. We conclude that AMPK activation appears to induce increased UCP expression, and that such an effect is mediated through an interaction with a specific portion of the UCP3 promoter. These findings support the idea that some degree of the cardioprotective effects observed with AMPK activation may be due to increased UCP expression in the heart.
Laskowski, Karl, "The Regulation of Mitochondrial Uncoupling Proteins in the Heart" (2009). Yale Medicine Thesis Digital Library. 430.