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bioRxiv · 10.1101/2025.04.19.649660

Prevention and reversal of hypertension-induced coronary microvascular dysfunction by a plant-based diet

Najjar, R. S.·Hekmatyar, K.·Wang, Y.·Ngo, V. L.·Lail, H.·Tejada, J. P.·Danh, J. P.·Wanders, D.·Feresin, R. G.·Mehta, P. K.·Gewirtz, A.
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Abstract

Background and aimsCoronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes. CMD is driven by endothelial and vascular smooth muscle cell (VSMC) dysfunction. We aimed to test whether CMD could be mitigated by a plant-based diet (PBD) in an animal model of hypertension. MethodsWe compared 28- and 40-week-old female normotensive Wistar-Kyoto and spontaneously hypertensive (SHR) rats, maintained, from age 4 weeks, on a control refined diet or a PBD, comprised of 28% fruits, vegetables, nuts and legumes. A subset of control SHRs were switched to the PBD at 28 weeks. CMD was assessed by coronary flow reserve via echocardiogram. Cardiac microvascular endothelial function was assessed via cMRI. Endothelial and VSMC function were assessed in the left ventricle (LV) or in isolated VSMCs. The role of gut microbiota was probed via 16S sequencing and antibiotics. Cardiac inflammation, oxidative stress, and fibrosis were also explored. ResultsSHRs exhibited endothelial dysfunction and likely VSMC dysfunction. PBD did not ameliorate their hypertension but, nonetheless, prevented and reversed CMD. PBDs mitigation of CMD was associated with improved endothelial nitric oxide synthase function and NO-mediated VSMC signaling, as well as reductions in LV oxidative stress, inflammatory signaling, and fibrosis. PBD altered the gut microbiota, although antibiotic studies failed to establish its importance in ameliorating CMD. ConclusionsA PBD prevented CMD development and reversed established CMD in SHRs. Such benefits of PBD, which occurred without alleviating hypertension, were possibly due to improved endothelial function and likely improved VSMC function. These results support clinical trials to test PBDs in human CMD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/649660v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a87550org.highwire.dtl.DTLVardef@add809org.highwire.dtl.DTLVardef@1426561org.highwire.dtl.DTLVardef@de9e0_HPS_FORMAT_FIGEXP M_FIG C_FIG A plant-based diet prevented and reversed CMD without attenuating hypertension. Such amelioration of CMD was not negated by antibiotics and correlated with improved endothelial and VSMC function. Legend: ABX, antibiotics; BP, blood pressure; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PBD, plant-based diet; PKG, protein kinase G; PLN, phospholamban; SHR, spontaneously hypertensive rat; SR, sarcoplasmic reticulum; VSMC, vascular smooth muscle cell.

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Najjar, R. S., Hekmatyar, K., Wang, Y., Ngo, V. L., Lail, H., Tejada, J. P., Danh, J. P., Wanders, D., Feresin, R. G., Mehta, P. K., Gewirtz, A.. 2025-04-24. Prevention and reversal of hypertension-induced coronary microvascular dysfunction by a plant-based diet. https://doi.org/10.1101/2025.04.19.649660

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