AKT Mediates Adiponectin-Dependent Regulation of VSMC Phenotype

Author:

Cullen Abigail E.12ORCID,Centner Ann M.1ORCID,Deitado Riley1,Ismaeel Ahmed3,Koutakis Panagiotis4ORCID,Muller-Delp Judy5,Salazar Gloria16ORCID

Affiliation:

1. Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32306, USA

2. Department of Human Physiology, University of Oregon, Eugene, OR 97403, USA

3. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA

4. Department of Biology, Baylor University, Waco, TX 76706, USA

5. Department of Biological Sciences, Florida State University, Tallahassee, FL 32306, USA

6. Center for Advancing Exercise and Nutrition Research on Aging (CAENRA), Florida State University, Tallahassee, FL 32306, USA

Abstract

Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype of vascular smooth muscle cells (VSMCs). However, the lack of adiponectin or its receptor and treatment with recombinant adiponectin have shown contradictory effects on plaque in mice. RNA sequence of Adipoq+/+ and adipoq−/− VSMCs from male aortas identified a critical role for adiponectin in AKT signaling, the extracellular matrix (ECM), and TGF-β signaling. Upregulation of AKT activity mediated proliferation and migration of adipoq−/− cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration of adipoq−/− cells but did not improve the expression of contractile genes. Adiponectin deficiency impaired oxidative phosphorylation (OXPHOS), increased expression of glycolytic enzymes, and elevated mitochondrial reactive oxygen species (ROS) (superoxide, and hydrogen peroxide). Anti-atherogenic mechanisms targeted the ECM in adipoq−/− cells, downregulating MMP2 and 9 and upregulating decorin (DCN) and elastin (ELN). In vivo, the main sex differences in protein expression in aortas involved a more robust upregulation of MMP3 in females than males. Females also showed a reduction in DCN, which was not affected in males. Our study uncovered the AKT/MAPK/TGF-β network as a central regulator of VSMC phenotype.

Funder

USDA-AFRI

Florida Department of Health, James and Esther King Biomedical Research Program

Publisher

MDPI AG

Subject

General Medicine

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