Abstract 15987: CD74 Knockout Rescues Against Obesity-Induced Cardiac Hypertrophy and Contractile Dysfunction: Role of Autophagy and ER Stress
Obesity, which is characterized by continuous energy and nutrient exposure, triggers metabolic and oxidative stress, inflammatory response and increased risk of heart disease. CD74, the main component of the cytokine macrophage migration inhibitory factor (MIF) receptor family, plays a crucial role in inflammatory diseases. Autophagy, a lysomal-dependent pathway of degradation, is responsible for the turnover of long-lived proteins and damaged or functionally redundant intracellular structures. A tie between autophagy and immune response has been reported, which may underlie obesity-induced cardiac dysfunction. This study was designed to examine the role of CD74 in high fat diet-induced obesity, cardiac geometric and functional changes. Wild-type (WT) and CD74 knockout (CD74-/-) mice were fed high fat (45% calorie) or low fat (10% calorie) diet for 5 months prior to assessment of body weight, IPGTT, cardiac lipid accumulation and contractile function. Expression of autophagic signaling proteins including mTOR, AMPK, Akt, LC3, Atg5, Atg7, Beclin-1,p62 and ER stress markers p-eIF2α, CHOP, p-IRE1αwas evaluated. High fat diet induced body weight gain, fat tissue deposition, insulin resistance, cardiac lipid accumulation, increased serum cholesterol level, depressed myocardial contractile capacity, the effects of which were blunted by CD74 knockout. Western blot analysis revealed upregulated expression of p-mTOR, P62, p-eIF2α, CHOP, p-IRE1α and as well as decreased levels of phosphorylated-AMPK, LC3II, Atg5, and Atg7 in high fat-WT mouse hearts, the effects of which were blunted by CD74-/- mice. To understand the cause-effect relationship between ER stress and autophagy, H9c2 cells were tranfected with Atg5 siRNA. Expression of ER stress markers were significantly increased accompanied by an increased expression of p62 and downregulation of LC3II. In contrary to the previous notion that ER stress induces autophagy to degrade unfolded proteins and remove superfluous ER membranes, our data showed that CD74 knockout rescued high fat diet-induced obesity, insulin resistance, cardiac lipid accumulation and dysfunction possibly through downregulation of autophagy-mediated ER stress.
- © 2011 by American Heart Association, Inc.