Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation
Boa Kim, … , Garret A. FitzGerald, Zoltan Arany
Boa Kim, … , Garret A. FitzGerald, Zoltan Arany
Published October 12, 2023
Citation Information: J Clin Invest. 2023;133(24):e173160. https://doi.org/10.1172/JCI173160.
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Research Article Cardiology

Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation

Abstract

Metabolic syndrome, today affecting more than 20% of the US population, is a group of 5 conditions that often coexist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here, we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo and blunts blood pressure elevation in response to a high-fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.

Authors

Boa Kim, Wencao Zhao, Soon Y. Tang, Michael G. Levin, Ayon Ibrahim, Yifan Yang, Emilia Roberts, Ling Lai, Jian Li, Richard K. Assoian, Garret A. FitzGerald, Zoltan Arany

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Figure 7

Suppression of LD formation rescues the induction of BP by endothelial ATGL deletion or by HFD.

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Suppression of LD formation rescues the induction of BP by endothelial A...
(A) En face staining of portal vein (upper panel) and whole-mount staining of capillary vessels in the soleus (lower panel) after DMSO versus iDGAT1 injection in Atgl ECKO mice. iDGAT1 was given at 3 mg/kg via i.p. injection. BODIPY staining (green) indicates neutral lipids, and CD31 (red) marks the endothelium. BODIPY-positive area in the endothelium is quantified. *P < 0.05; **P < 0.01, t test. n = 4–5 mice/group. (B) eNOS mRNA levels measured in isolated ECs from lung of WT versus Atgl ECKO mice after a week of DMSO versus iDGAT1 injection. n = 3. *P < 0.05, 1-way ANOVA. (C) Nitrate and nitrite levels measured in the plasma of WT versus Atgl ECKO mice after a week of DMSO or iDGAT1 injection (3 mg/kg i.p.). **P < 0.01, 1-way ANOVA. n = 3–4 mice/group. (D) En face staining of portal vein (upper panel) and whole-mount staining of capillary vessels in the soleus (lower panel) after DMSO versus iDGAT1 injection (3 mg/kg i.p.) in C57BL/6J WT mice maintained on a 3-day HFD. BODIPY staining (green) indicates neutral lipids, and CD31 (red) marks the endothelium. BODIPY-positive area in the endothelium is quantified on the right. n = 4–5. ***P < 0.001; ****P < 0.0001, t test. (E) Experimental setup of daily administration of DMSO or iDGAT1 in C57BL/6J WT mice while providing NC or HFD+HSD. (F) Elevation of SBP during the active phase while provided with the indicated diet. ****P < 0.0001, 2-way ANOVA. n = 5 mice/group. (G) Average active phase SBP while provided with the indicated diet. *P < 0.05, 1-way ANOVA. n = 5 mice/group.