75-OR: Dietary Nitrate and Fecal Transplantation Prevent Cardiac Dysfunction and Attenuate Left Ventricular Mitochondrial Reactive Oxygen Species Emission in High-Fat Diet-Fed Mice

Abstract

Cardiometabolic diseases are multifactorial conditions involving dysfunction within the left ventricle (LV), adipose tissue (AT), and gut microbiome. Nitrate supplementation has been shown to influence cardiac contractility, mitochondrial function, and microbial populations, effects which require commensal gut bacteria to metabolize nitrate. Therefore, we examined if dietary nitrate and fecal microbial transplant (FMT) from nitrate-fed mice were capable of preventing high fat diet (HFD) induced cardiac abnormalities. Male C57Bl/6N mice were fed a control diet, or HFD (60% fat) in the absence or presence of 4mM sodium nitrate in drinking water for 8 weeks. A further subset of HFD-fed mice were gavaged with feces from HFD+nitrate donors or HFD donors for 3 days at the beginning of week 7, and followed until week 8. Compared to controls, HFD mice presented with ∼25% reduction in end diastolic volume, stroke volume, and cardiac output, in association with an increase in cardiac fibrosis, AT inflammation, and serum lipids. In contrast, dietary nitrate prevented these detrimental effects. The improvement in cardiac function following dietary nitrate was not attributed to changes in LV mitochondrial respiration, however, nitrate prevented the increase in LV mitochondrial reactive oxygen species (ROS) emission associated with HFD. While FMT from HFD+nitrate donors did not influence AT inflammation or cardiac fibrosis, HFD+nitrate FMT decreased serum lipids, LV ROS, and improved cardiac function compared to FMT from HFD-fed donors, without increasing serum nitrate concentrations. Altogether, dietary nitrate prevents the detriments of HFD on cardiac function and LV mitochondrial ROS emission, effects which may not be directly dependent on increasing serum nitrate. Rather, the beneficial effects of nitrate may be linked to changes in the gut microbiome, as FMT from nitrate-fed donors improved LV function. Disclosure H.L. Petrick: None. H. Brunetta: None. A. Kirsh: None. P. Barbeau: None. L.M. Ogilvie: None. J. Simpson: None. J.D. Schertzer: None. G. Holloway: None. Funding Natural Sciences and Engineering Research Council of Canada (400362)