Physical activity opposes coronary vascular dysfunction induced during high fat feeding in mice

Key points Sedentary and high‐fat diet lifestyles are associated with greater prevalence of obesity and type 2 diabetes in humans, both of which independently increase atherosclerosis. High‐fat diet in sedentary individuals produces endothelial dysfunction in blood vessels as a first step toward coronary arteriosclerosis. We observed preservation of coronary arteriolar vascular function when mice began voluntary running in wheels at the start of a high‐fat diet. We further showed that mechanisms by which running opposed the detrimental effects of high‐fat diet on vascular function included maintenance of eNOS phosphorylation, leptin sensitivity, and redox balance in mouse coronary arterioles. The results provide evidence for how physical activity is an effective therapy to oppose the development of atherosclerosis in the first place. Abstract The study's purpose was to investigate if physical activity initiated with the start of high‐fat feeding would oppose development of endothelial dysfunction, and if it does, then to determine some potential mechanisms. C57BL/6 female mice were randomly divided into three groups: (1) control low‐fat diet (LF‐SED; 15% of calories from fat), (2) high‐fat diet (HF‐SED; 45% of calories from fat), and (3) HF diet given access to a voluntary running wheel (HF‐RUN). Our hypothesis was that HF‐RUN would differ in multiple markers of endothelial dysfunction from HF‐SED after 10 weeks of 45%‐fat diet, but would not differ from LF‐SED. HF‐RUN differed from HF‐SED in nine determinations in which HF‐SED either had decreases in (1) acetylcholine (ACh)‐induced and flow‐induced vasodilatations in isolated, pressurized coronary arterioles, (2) heart phosphorylated endothelial nitric oxide synthase (p‐eNOS/eNOS) protein, (3) coronary arteriole leptin ( ob ) receptor protein, (4) phosphorylated signal transducer and activator of transcription 3 (p‐STAT3/STAT3) protein, and (5) coronary arteriole superoxide dismutase 1 protein; or had increases in (6) percentage body fat, (7) serum leptin, (8) coronary arteriole suppressor of cytokine signalling 3 (SOCS3) protein, and (9) coronary arteriole gp91 phox protein. Higher endothelium‐dependent vasodilatation by ACh or leptin was abolished with incubation of NOS inhibitor N G ‐nitro‐ l ‐arginine‐methyl ester ( l ‐NAME) in LF‐SED and HF‐RUN groups. Further, impaired ACh‐induced vasodilatation in HF‐SED was normalized by apocynin or TEMPOL to LF‐SED and HF‐RUN. These findings demonstrate multiple mechanisms (eNOS, leptin and redox balance) by which voluntary running opposes the development of impaired coronary arteriolar vasodilatation during simultaneous high‐fat feeding.