Fat intake modifies vascular responsiveness and receptor expression of vasoconstrictors: implications for diet-induced obesity.
OBJECTIVE
Angiotensin II (Ang II), endothelin-1 (ET-1) and reactive oxygen species (ROS) have been implicated in the development of pathologic changes associated with obesity including hypertension and atherosclerosis. The aim of this study was to investigate the effects of dietary fat content on vasoreactivity and receptor expression at the level of gene and protein expression.


METHODS
C57BL/6 mice were fed diets of normal (Control, 12.3% kcal from fat), high (HF, 41% kcal from fat) and very high (VHF, 58% kcal from fat) fat content for 15 weeks. Glucose tolerance tests were performed, and aortic rings were exposed to ET-1 (0.01-300 nM) and Ang II (100 nM) in the presence of L-nitro-arginine-methyl ester (L-NAME; 300 microM). Gene and protein expressions of angiotensin and endothelin receptors were examined by real-time PCR and immunoblotting, respectively. The effects of diet on responses to acetylcholine (ACh 0.1-300 microM), in the absence or presence of L-NAME, and to exogenous ROS/.OH were also investigated.


RESULTS
Both high fat diets similarly impaired glucose tolerance (P<0.05). Increasing dietary fat augmented contractions to Ang II in a step-wise manner (P<0.05). Conversely, increasing dietary fat had no effect on contractions to ET-1. Exposure to ROS/.OH resulted in a rapid vasodilation that was markedly augmented in a step-wise manner with increasing dietary fat (P<0.05). Endothelium-dependent relaxation to ACh was unaffected whereas vasoconstriction to high concentrations of ACh was enhanced in VHF animals (P<0.05 vs. control). Gene expression of the AT(1B) receptor was increased in the aorta of VHF mice, and aortic ET(A) receptor protein expression was increased after both high fat diets.


CONCLUSIONS
These findings demonstrate that changes in dietary fat intake modulate vascular reactivity in response to Ang II and ROS, as well as expression of vascular angiotensin and endothelin receptors. Dietary fat intake may thereby directly affect cardiovascular risk.
Mundy
Alexa L
AL
Department of Medicine, Internal Medicine I, Medical Policlinic, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
Haas
Elvira
E
Bhattacharya
Indranil
I
Widmer
Corinne C
CC
Kretz
Martin
M
Hofmann-Lehmann
Regina
R
Minotti
Roberta
R
Barton
Matthias
M
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D015153:Blotting, Western / Q000379:methods; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D017665:Hydroxyl Radical / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009765:Obesity / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D004041:Dietary Fats; D019332:Endothelin-1; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D017665:Hydroxyl Radical; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester