Increased myocardial susceptibility to repetitive ischemia with high-fat diet-induced obesity.

Obesity and diabetes are frequently associated with cardiovascular disease. When a normal heart is subjected to brief/sublethal repetitive ischemia and reperfusion (I/R), adaptive responses are activated to preserve cardiac structure and function. These responses include but are not limited to alterations in cardiac metabolism, reduced calcium responsiveness, and induction of antioxidant enzymes. In a model of ischemic cardiomyopathy inducible by brief repetitive I/R, we hypothesized that dysregulation of these adaptive responses in diet-induced obese (DIO) mice would contribute to enhanced myocardial injury. DIO C57BL/6J mice were subjected to 15 min of daily repetitive I/R while under short-acting anesthesia, a protocol that results in the development of fibrotic cardiomyopathy. Cardiac lipids and candidate gene expression were analyzed at 3 days, and histology at 5 days of repetitive I/R. Total free fatty acids (FFAs) in the cardiac extracts of DIO mice were significantly elevated, reflecting primarily the dietary fatty acid (FA) composition. Compared with lean controls, cardiac FA oxidation (FAO) capacity of DIO mice was significantly higher, concurrent with increased expression of FA metabolism gene transcripts. Following 15 min of daily repetitive I/R for 3 or 5 days, DIO mice exhibited increased susceptibility to I/R and, in contrast to lean mice, developed microinfarction, which was associated with an exaggerated inflammatory response. Repetitive I/R in DIO mice was associated with more profound significant downregulation of FA metabolism gene transcripts and elevated FFAs and triglycerides. Maladaptive metabolic changes of FA metabolism contribute to enhanced myocardial injury in diet-induced obesity.

CHARACTERIZATION OF THE ROLE OF CARMA3 IN ENDOPLASMIC RETICULUM STRESS-INDUCED NF-κB ACTIVATION

Endoplasmic reticulum (ER) stress-induced inflammation plays an important role in the progression of many diseases, such as type II diabetes, insulin resistance, cancers, and so on. NF-κB is believed to be a central regulator of ER stress-induced inflammation. However, studies on how ER stress induces NF-κB activation are limited and, in some cases, controversial. In the present study, we utilized two commonly used ER stress inducers, thapsigargin and tunicamycin, to study the mechanism. We found that two caspase-recruitment domain (CARD)-containing proteins, CARMA3 and BCL10, play a crucial roles on ER stress-induced NF-κB activation by regulating IκBα kinase activity. Consistently, we observed that a physiological ER stress inducer, hypoxia, could activate NF-κB in a CARMA3-dependent manner. Additionally, we showed that the activation of the UPR signaling pathways were intact in both CARMA3- and BCL10-deficient cells under ER stress. Together, this study provides insight into the mechanism of how ER stress induces NF-κB activation. It allows us to better understand ER stress-induced inflammation and develop the corresponding therapeutic interference to treat diseases