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Absence of Gravin Mediated Signaling Inhibits Development of High Fat Diet-Induced Hyperlipidemia and Atherosclerosis.

Qiying Fan,Xing Yin,Abeer M. Rababa’h,Andrea Diaz Diaz,Cori S. Wijaya,Sonal Singh,Santosh V. Suryavanshi,H. Vo,Moawiz Saeed,Yang Zhang,B. McConnell

Published 2019 in American Journal of Physiology. Heart and Circulatory Physiology

ABSTRACT

Gravin, an A-kinase anchoring protein (AKAP), is known to play a role in regulating key processes that lead to inflammation and atherosclerosis development; namely, cell migration, proliferation, and apoptosis. We investigated the role of gravin in the development of high-fat-diet (HFD) induced atherosclerosis and hyperlipidemia. Five-week-old male wild-type (WT) and gravin-t/t mice were fed normal-diet (ND) or HFD for 16-weeks. Gravin-t/t mice showed significantly lower liver-to-body-weight ratio, cholesterol, triglyceride, and very low-density lipoprotein levels in serum as compared to WT mice on HFD. Further, there was less aortic plaque formation coupled with decreased lipid accumulation and liver damage as the gravin-t/t mice had lower levels of serum alanine aminotransferase and aspartate aminotransferase. Additionally, gravin-t/t HFD-fed mice had decreased expression of liver HMG-CoA reductase, an essential enzyme for cholesterol synthesis and lower fatty acid synthase expression. Gravin-t/t HFD-fed mice also exhibited inhibition of sterol regulatory element binding protein-2 (SREBP-2) expression, a liver transcription factor associated with the regulation of lipid transportation. In response to platelet-derived growth factor receptor treatment, gravin-t/t vascular smooth muscle cells exhibited lower intracellular calcium transients and decreased PKA and PKC-dependent substrate phosphorylation, notably involving the Erk1/2 signaling pathway. Collectively, these results suggest the involvement of gravin-dependent regulation of lipid metabolism via the reduction of SREBP-2 expression. The absence of gravin-mediated signaling lowers blood pressure, reduces plaque formation in the aorta, and decreases lipid accumulation and damage in the liver of HFD mice. Through these processes, the absence of gravin-mediated signaling complex delays the HFD-induced hyperlipidemia and atherosclerosis.

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