期刊
HYPERTENSION
卷 77, 期 4, 页码 1191-1202出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.120.16237
关键词
hypertension; microbiota; mitochondria; rats; inbred Dahl; vascular remodelling
资金
- National Science Foundation-Northern Ohio Alliance for Graduate Education and the Professoriate [NOA-AGEP: 1432878]
- National Institutes of Health-National Institute of General Medical Sciences [NIGMS: R00GM11888]
- National Heart, Lung, and Blood Institute [NHLBI: R01HL149762, R01HL1430820, K99HL151889]
- National Cancer Institute [NCI: R01CA219144]
- American Heart Association [18POST34060003]
Cell death has been a characteristic phenotype of organ damage in hypertension, while leaky gut has recently been revealed as a novel hypertensive phenotype. Both mitochondria and bacteria produce NFPs, which activate FPR-1 to contribute to hypertension pathophysiology.
Cell death has long been a characteristic phenotype of organ damage in hypertension, and recently, leaky gut has been revealed as a novel hypertensive phenotype. However, despite the increase in bacterial and damaged mitochondrial products in the circulation of hypertensive patients and animals, the mechanistic contribution of these two phenomena to hypertension pathophysiology is unknown. Mitochondria and bacteria both start protein translation with an N-formyl methionine residue and thus are the only sources of NFPs (N-formyl peptides), which activate the FPR-1 (formyl peptide receptor-1). We hypothesized that the synergistic action of bacterial and mitochondrial NFPs would cause the spontaneous elevation of blood pressure and vascular remodeling in male Dahl salt-sensitive rats via FPR-1. We observed that mitochondria-derived peptides originating from cell death in the kidneys are responsible for FPR-1-induced vascular hypercontractility and remodeling and premature elevation of BP in Dahl salt-sensitive rats fed a low-salt diet. However, a high-salt diet leads to gut barrier disruption and, subsequently, a synergistic action of mitochondria, and bacteria-derived leaky gut NFPs lead to a severe and established hypertension. Administration of an FPR-1 antagonist lowered blood pressure in Dahl salt-sensitive rats on a low-salt diet but amoxicillin administration did not. These results reveal for the first time that cell death can be a cause of hypertensive pathophysiology, whereas leaky gut is a consequence.
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