AKT Mediates Adiponectin-Dependent Regulation of VSMC Phenotype

Abigail E Cullen; Ann M Centner; Riley Deitado; Ahmed Ismaeel; Panagiotis Koutakis; Judy Muller-Delp; Gloria Salazar

doi:10.3390/cells12202493

AKT Mediates Adiponectin-Dependent Regulation of VSMC Phenotype

Cells. 2023 Oct 20;12(20):2493. doi: 10.3390/cells12202493.

Authors

Abigail E Cullen^{1

2}, Ann M Centner¹, Riley Deitado¹, Ahmed Ismaeel³, Panagiotis Koutakis⁴, Judy Muller-Delp⁵, Gloria Salazar^{1

6}

Affiliations

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.

Keywords: AKT; adiponectin; atherosclerosis; sex; vascular smooth muscle cells.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adiponectin* / genetics
Adiponectin* / metabolism
Animals
Female
Male
Mice
Muscle, Smooth, Vascular / metabolism
Phenotype
Proto-Oncogene Proteins c-akt* / metabolism
Transforming Growth Factor beta / metabolism

Substances

Adiponectin
Proto-Oncogene Proteins c-akt
Transforming Growth Factor beta

Grants and funding

This research was funded by the USDA-AFRI, GRANT12444832 and the Florida Department of Health, James and Esther King Biomedical Research Program (9JK01).