Gravin Scaffolding Protein Mediates Signaling during Atherosclerosis

Atherosclerosis is an inflammatory response that principally in the walls of arteries, contributing to cardiovascular mortality, which can lead to growth factors over-release. Gravin, an A-Kinase Anchoring Proteins, targets Protein Kinase A (PKA), Protein Kinase C (PKC), and Ca2+/Calmodulin-dependent Protein Kinase (CaMKII) and mediates intracellular signaling. This gravin coordinated kinase-dependent substrate phosphorylation leads to changes in intracellular Ca2+, which is associated with cell proliferation and migration. Additionally, recent studies show that gravin can regulate lipid metabolism in the liver and affects cell proliferation and migration.

To study the role of gravin in atherosclerosis, five 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. Furthermore, gravin-t/t (HFD) mice showed lower liver-to-body weight ratio as well as decreased lipid accumulation and decreased liver damage. In addition, gravin-t/t (HFD) mice showed lower genes expressions related to cholesterol biosynthesis via less activation of the sterol-regulatory-element-binding protein 2 (SREBP2). We also observed less aortic lipid accumulation and lower blood pressure in gravin-t/t (HFD) mice.

VSMCs, play a crucial role in the progression of atherosclerosis. Gravin-t/t VSMCs showed decreased Ang II induced VSMCs migration and proliferation when compared to WT VSMCs. We also observed less migration in Gravin-t/t VSMCs PDGF. Furthermore, gravin-t/t VSMCs exhibited decreased PKC activity and lower intracellular Ca2+ transients after either Ang II or PDGF treatment. These changes were accompanied by significant differences in PKC phosphorylation and PKC-dependent substrate phosphorylation, which involved ERK1/2 signaling pathway.

In conclusion, these findings indicated that the absence of gravin mediated signaling was able to decrease lipid metabolism and accumulation in the liver and lipid accumulation in the aorta as well as to lower the blood pressure in response to HFD. In addition, our findings indicated that in the absence of gravin mediated signaling, Ang II and PDGF induced VSMCs proliferation and migration were suppressed in gravin-t/t VSMCs. Taken together, our data indicates that gravin is involved in the initiation and progression of atherosclerosis and/or vascular remodeling.