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Circ Res ; 126(7): 839-853, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32078445


RATIONALE: High-salt diet is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt-induced hypertension (hSIH). However, the detailed roles of intestinal flora in hSIH pathogenesis have not yet been fully elucidated. OBJECTIVE: To reveal the roles and mechanisms of intestinal flora in hSIH development. METHODS AND RESULTS: The abovementioned issues were investigated using various techniques including 16S rRNA gene sequencing, untargeted metabolomics, selective bacterial culture, and fecal microbiota transplantation. We found that high-salt diet induced hypertension in Wistar rats. The fecal microbiota of healthy rats could dramatically lower blood pressure (BP) of hypertensive rats, whereas the fecal microbiota of hSIH rats had opposite effects. The composition, metabolism, and interrelationship of intestinal flora in hSIH rats were considerably reshaped, including the increased corticosterone level and reduced Bacteroides and arachidonic acid levels, which tightly correlated with BP. The serum corticosterone level was also significantly increased in rats with hSIH. Furthermore, the above abnormalities were confirmed in patients with hypertension. The intestinal Bacteroides fragilis could inhibit the production of intestinal-derived corticosterone induced by high-salt diet through its metabolite arachidonic acid. CONCLUSIONS: hSIH could be transferred by fecal microbiota transplantation, indicating the pivotal roles of intestinal flora in hSIH development. High-salt diet reduced the levels of B fragilis and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation. This study revealed a novel mechanism different from inflammation/immunity by which intestinal flora regulated BP, namely intestinal flora could modulate BP by affecting steroid hormone levels. These findings enriched the understanding of the function of intestinal flora and its effects on hypertension.

Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165649, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870714


Genome-wide changes in gene translational efficiency during the development of heart failure are poorly understood. We tested the hypothesis that aberrant changes in translational efficiency of cardiac genes are associated with the development of myocyte decompensation in response to persistent stress stimuli. We demonstrated that chronic pressure overload in mice resulted in a genome-wide reprogramming of translational efficiency, with >50% of the translatome exhibiting decreased translational efficiencies during the transition from myocardial compensation to decompensation. Importantly, these translationally repressed genes included those involved in angiogenesis and energy metabolism. Moreover, we showed that the stress-induced translational reprogramming was accompanied by persistent activation of the eukaryotic initiation factor 2α (eIF2α)-mediated stress response pathway. Counteracting the endogenous eIF2α functions by cardiac-specific overexpression of an eIF2α-S51A mutant ameliorated the development of myocyte decompensation, with concomitant improvements in translation of cardiac functional genes and increases in angiogenic responses. These data suggest that the mismatch between transcription and translation of the cardiac genes with essential functions may represent a novel molecular mechanism underlying the development of myocyte decompensation in response to chronic stress stimuli, and the eIF2α pathway may be a viable therapeutic target for recovering the optimal translation of the repressed cardiac genes.