Journal
DIABETES
Volume 64, Issue 11, Pages 3914-3926Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db15-0244
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Funding
- American Diabetes Association [1-12-BS-208, ADA 7-08-RA-164]
- National Institutes of Health (NIH) [2R15HL091493]
- University of Utah (UU) Office of the Vice President for Research
- UU College of Health
- American Heart Association [12BGIA8910006]
- NIH [R01 DK092065]
- American Physiological Society (APS) Undergraduate Research Program
- APS Undergraduate Research Excellence Fellowship Program
- APS STEP-UP Program
- American Heart Association Western States Affiliate Undergraduate Student Summer Research Program
- ADA Minority Undergraduate Internship Program
- Science Without Borders Program of the Government of Brazil
- Native American Research Internship Program
- UU Undergraduate Research Opportunities Program
- NIH Short-Term Training Students in Health Professional Schools Grant [T35 HL007744]
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Prior studies have implicated accumulation of ceramide in blood vessels as a basis for vascular dysfunction in diet-induced obesity via a mechanism involving type 2 protein phosphatase (PP2A) dephosphorylation of endothelial nitric oxide synthase (eNOS). The current study sought to elucidate the mechanisms linking ceramide accumulation with PP2A activation and determine whether pharmacological inhibition of PP2A in vivo normalizes obesity-associated vascular dysfunction and limits the severity of hypertension. We show in endothelial cells that ceramide associates with the inhibitor 2 of PP2A (I2PP2A) in the cytosol, which disrupts the association of I2PP2A with PP2A leading to its translocation to the plasma membrane. The increased association between PP2A and eNOS at the plasma membrane promotes dissociation of an Akt-Hsp90-eNOS complex that is required for eNOS phosphorylation and activation. A novel small-molecule inhibitor of PP2A attenuated PP2A activation, prevented disruption of the Akt-Hsp90-eNOS complex in the vasculature, preserved arterial function, and maintained normal blood pressure in obese mice. These findings reveal a novel mechanism whereby ceramide initiates PP2A colocalization with eNOS and demonstrate that PP2A activation precipitates vascular dysfunction in diet-induced obesity. Therapeutic strategies targeted to reducing PP2A activation might be beneficial in attenuating vascular complications that exist in the context of type 2 diabetes, obesity, and conditions associated with insulin resistance.
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