Grape phytochemical intake alters heart failure pathogenesis and cardiac gene transcription/translation.

摘要

High blood pressure or hypertension is a prevalent and significant contributor to morbidity and mortality from heart failure. The DASH (Dietary Approaches to Stop Hypertension) clinical trials provided evidence that diets rich in fruits and vegetables reduced blood pressure. Animal models of hypertension may permit mechanistic appraisals of the interaction of diet and disease. One recent study in hypertensive rats modeled the DASH diet using added vitamins and minerals, but failed to detect an effect upon blood pressure. Therefore, a whole foods model may be more appropriate to assess the effect of diet on hypertension, versus elevated vitamins and minerals, alone.;It is currently unknown if intake of phytochemical-rich whole foods affects hypertension-associated heart failure. This proposal uses whole table grapes as a model of a phytochemical-rich food. We first tested the hypothesis that a grape-enriched diet would impact the development of hypertension-related cardiac pathology in the Dahl Salt-Sensitive (Dahl-SS) rat model. Whole table grape powder (3% of diet) significantly lowered blood pressure, cardiac hypertrophy and cardiac oxidative damage. In addition, grape-fed rats displayed improved diastolic function and cardiac output. However, cardiac-specific mechanisms of these effects remain unknown.;Bioavailable grape phytochemicals may have reduced heart failure pathogenesis by altered cardiac cell signaling and gene transcription/translation. One project arm focuses on transcription factor peroxisome proliferator-activating receptor (PPAR). Cardiac PPAR isoforms are down-regulated with Dahl-SS rat heart failure, while cardiac pro-inflammatory transcription factor NFkappaB activity is elevated. Importantly, PPAR activation directly reduces NF-kappaB activation. Anthocyanins can activate PPARs in varied experimental models. If the anthocyanin-rich grape powder diet altered cardiac PPAR activity, it could also limit NF-kappaB activity and thereby reduce inflammation and fibrosis.;Bioavailable grape phytochemicals could also activate the phenol-responsive, aryl-hydrocarbon receptor (AhR), which binds to genomic xenobiotic response elements (XREs) and stimulates the transcription of mRNA related to antioxidant defense. Bioavailable grape phytochemicals could also activate NF-E2 p45-related factor (Nrf2), a transcription factor which binds genomic antioxidant-responsive elements (AREs) and like AhR, stimulates the transcription of genes related to antioxidant defense. While AhR/XRE and Nrf2/ARE interactions have been shown in vitro with select phytochemicals, it is uncertain if physiologically-relevant doses of grape powder could confer a similar effect in vivo.;Four groups were studied: low salt diet + grape, high salt + grape, and their respective low-salt and high-salt, carbohydrate-equivalent controls. Grape diets enhanced cardiac PPAR and reduced NF-kappaB activity, NF-kappaB-related mRNA, and TNF-alpha and TGF-beta expression. Grape diets also enhanced cardiac AhR and Nrf2 activation, related mRNA, and glutathione dynamics. Importantly, the majority of these effects were conserved between low salt grape and high salt grape groups, indicating specific effects from the grape powder treatment. In summary, consumption of whole table grape powder reduced Dahl-SS rat cardiac hypertensive pathology and altered gene transcription/translation related to inflammation, fibrosis, and glutathione antioxidant defense.