Gravin Scaffolding Protein Mediates Signaling Involved in theRegulation of Hyperlipidemia and Atherosclerosis

Abstract

Atherosclerosis is a leading health problem and contributes to cardiovascular related mortality. Furthermore, hyperlipidemia is a major atherogenic factor.Understanding the cellular mechanisms leading to atherosclerosis is still lacking. Gravin (AKAP12), an A‐kinase anchoring protein (AKAP), scaffolds and targets various signaling proteins to specific intracellular locations and has been implicated in mediating lipid metabolism. Thus, the purpose of this study was to determine whether the absence of gravin‐mediated signaling would prevent the initiation and progression of atherosclerosis.5 week‐old wild‐type (WT) and gravin‐truncated (gravin‐t/t) mice were subjected to high fat diet (HFD) or normal diet (ND) for 16‐weeks. Cholesterol, triglyceride and VLDL level in serum were significantly decreased in gravin‐t/t HFD compared to WT HFD mice. In addition, systolic and diastolic blood pressure was also lower in gravin‐t/t HFD mice.Furthermore, gravin‐t/t HFD mice showed lower liver‐to‐body weight ratio as well as decreased lipid accumulation and liver damage.These observations are consistent with the lower serum alanine aminotransferase(ALT) and aspartate aminotransferase (AST) levels identified in gravin‐t/t HFD mice. In addition, gravin‐t/t HFD mice had decreased expression of the active form of sterol‐regulatory‐element‐binding protein 2 (SREBP2), which resulted in lower HMG‐CoA reductase (HMGCR) and low‐density lipoprotein receptor (LDLR) expression. Finally, we observed less aortic lipid accumulation in gravin‐t/t HFD mice. Our data indicates that the absence of gravin mediated signaling were resistance to hyperlipidemia and prevented the progression of atherosclerosis.