Cardiovascular disease is the leading cause of death worldwide. Despite extensive interests and tremendous efforts, our understanding of heart disease remains rather limited.
Understanding the mechanisms of heart disease can ultimately lead to prevention and therapeutics. We employ multiple approaches, including mouse genetics, tissue culture, imaging, and molecular biology, to study several types of cardiovascular disease and injury.
Ischemic heart disease is highly prevalent in both developed and developing countries. Occlusion of coronary arteries leads to deprivation of nutrients and oxygen in certain areas of heart. Over time, cardiomyocytes undergo cell death.
Timely and efficient reperfusion of the occluded coronary artery is the most effective means to mitigate cardiac damage and improve clinical outcomes. However, reperfusion per se causes additional damage, which can account for up to 40 percent of the final infarct size. Clinical therapeutic approaches against this ischemia/reperfusion (I/R) injury are lacking.
We found the adaptive unfolded protein response (UPR) is potently activated by I/R in heart. We have shown that the spliced Xbp1 (Xbp1s) branch of the UPR confers strong cardiac protection against I/R injury. Mechanistically, we identified the downstream targets of Xbp1s, which mediates the beneficial effects of Xbp1s.
Gfat1, the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), is directly stimulated by transcriptional factor Xbp1s. The HBP is responsive to synthesize UDP-GlcNAc, the sole substrate for O-GlcNAc post-translational protein modification. Studies have shown that O-GlcNAc modification exerts protection against various stresses in cells. We are now studying the underlying mechanisms by which O-GlcNAcylation prevents cell death, using both in vitro and in vivo approaches.
In response to high blood pressure, the heart manifests hypertrophic growth to ameliorate wall stress. This adaptive cardiac hypertrophy may progress into maladaptive heart failure, but mechanisms governing the transition remain elusive. We believe metabolic alterations play a critical role in this process, so we are examining the role of glucose metabolism in cardiac hypertrophy and heart failure.
Diabetes and Heart Disease
Two-thirds of diabetic patients develop heart disease and may die of it. We are interested in cardiac remodeling in diabetes. In particular, we focus on the role of the UPR and glucose metabolism in this process.