Recently, the potential role of gut microbiome in metabolic diseases has been revealed, especially in cardiovascular diseases. Hypertension is one of the most prevalent cardiovascular diseases worldwide, yet whether gut microbiota dysbiosis participates in the development of hypertension remains largely unknown. To investigate this issue, we carried out comprehensive metagenomic and metabolomic analyses in a cohort of 41 healthy controls, 56 subjects with pre-hypertension, 99 individuals with primary hypertension, and performed fecal microbiota transplantation from patients to germ-free mice. Compared to the healthy controls, we found dramatically decreased microbial richness and diversity, Prevotella-dominated gut enterotype, distinct metagenomic composition with reduced bacteria associated with healthy status and overgrowth of bacteria such as Prevotella and Klebsiella, and disease-linked microbial function in both pre-hypertensive and hypertensive populations. Unexpectedly, the microbiome characteristic in pre-hypertension group was quite similar to that in hypertension. The metabolism changes of host with pre-hypertension or hypertension were identified to be closely linked to gut microbiome dysbiosis. And a disease classifier based on microbiota and metabolites was constructed to discriminate pre-hypertensive and hypertensive individuals from controls accurately. Furthermore, by fecal transplantation from hypertensive human donors to germ-free mice, elevated blood pressure was observed to be transferrable through microbiota, and the direct influence of gut microbiota on blood pressure of the host was demonstrated. Overall, our results describe a novel causal role of aberrant gut microbiota in contributing to the pathogenesis of hypertension. And the significance of early intervention for pre-hypertension was emphasized.

Aims. Hydrogen sulfide (H2S) has a protective role in the pathogenesis of atherosclerosis by multiple pathways. Sirtuin-1 (SIRT1) is a histone deacetylase, as an essential mediated longevity gene, and has an anti-atherogenic effect by regulating the acetylation of some functional proteins. Whether SIRT1 is involved in protecting H2S in atherosclerosis and its mechanism remains unclear. Results. In ApoE-knockout atherosclerosis mice, treatment with an H2S donor (NaHS or GYY4137) reduced atherosclerotic plaque area, macrophage infiltration, aortic inflammation and plasma lipid level. H2S treatment increased aorta and liver SIRT1 mRNA expression. Overexpression or slicing cystathionine gamma lyase (CSE) also changed intracellular SIRT1 expression. CSE/H2S treatment increased SIRT1 deacetylation in endothelium and hepatocytes and macrophages, then induced deacetylation of its target proteins (P53, P65 and sterol response element binding protein), thereby reducing endothelial and macrophage inflammation and inhibiting macrophage cholesterol uptake and cholesterol de novo synthesis of liver. Also, CSE/H2S induced SIRT1 sulfhydration at its 2 zinc finger domains, increased its zinc ion binding activity to stabilize the alpha-helix structure; and lowered its ubiquitination and reduced its degradation. Innovation. H2S is a novel SIRT1 activator by direct sulfhydration. Because SIRT1 has a role in longevity, H2S may be a protector for aging-related diseases. Conclusion. Endogenous CSE/H2S directly sulfhydrated SIRT1, enhanced SIRT1 binding to zinc ion, then promoted its deacetylation activity and increased SIRT1 stability, thus reducing atherosclerotic plaque formation.

To assess the global changes in and characteristics of the transcriptome of long noncoding RNAs (LncRNAs) in heart tissue, whole blood and plasma during heart failure (HF) and association with expression of paired coding genes. Here we used microarray assay to examine the transcriptome of LncRNAs deregulated in the heart, whole blood, and plasma during HF in mice. We confirmed the changes in LncRNAs by quantitative PCR. We revealed and confirmed a number of LncRNAs that were deregulated during HF, which suggests a potential role of LncRNAs in HF. Strikingly, the patterns of expression of LncRNA differed between plasma and other tissue during HF. LncRNA expression was associated with LncRNA length in all samples but not in plasma during HF, which suggests that the global association of LncRNA expression and LncRNA length in plasma could be biomarkers for HF. In total, 32 LncRNAs all expressed in the heart, whole blood and plasma showed changed expression with HF, so they may be biomarkers in HF. In addition, sense-overlapped LncRNAs tended to show consistent expression with their paired coding genes, whereas antisense-overlapped LncRNAs tended to show the opposite expression in plasma; so different types of LncRNAs may have different characteristics in HF. Interestingly, we revealed an inverse correlation between changes in expression of LncRNAs in plasma and in heart, so circulating levels of LncRNAs may not represent just passive leakage from the HF heart but also active regulation or release of circulatory cells or other cells during HF. We reveal stable expression of LncRNAs in plasma during HF, which suggests a newly described component in plasma. The distinct expression patterns of circulatory LncRNAs during HF indicate that LncRNAs may actively respond to stress and thus serve as biomarkers of HF diagnosis and treatment.

The aim of the present study was to investigate the effect of hydrogen sulfide (H₂S) signaling by nitric oxide (NO) in isolated rat aortas and cultured human umbilical vein endothelial cells (HUVECs). Both administration of H₂S and NaHS, as well as endogenous H₂S, reduced NO formation, endothelial nitric oxide synthase (eNOS) activity, eNOS transcript abundance, and l-arginine (l-Arg) transport (all P < 0.01). The kinetics analysis of eNOS activity and l-Arg transport showed that H₂S reduced V_max values (all P < 0.01) without modifying K_m parameters. Use of selective NOS inhibitors verified that eNOS [vs. inducible NOS (iNOS) and neuronal NOS (nNOS)] was the specific target of H₂S regulation. H₂S treatment (100 μmol/l) reduced Akt phosphorylation and decreased eNOS phosphorylation at Ser1177. H₂S reduced l-Arg uptake by inhibition of a system y+ transporter and decreased the CAT-1 transcript. H₂S treatment reduced protein expression of eNOS but not of nNOS and iNOS. Pinacidil (K_ATP channel opener) exhibited the similar inhibitory effects on the l-Arg/NOS/NO pathway. Glibenclamide (K_ATP channel inhibitor) partly blocked the inhibitory effect of H₂S and pinacidil. An in vivo experiment revealed that H₂S downregulated the vascular l-Arg/eNOS/NO pathway after intraperitoneal injection of NaHS (14 μmol/kg) in rats. Taken together, our findings suggest that H₂S downregulates the vascular l-Arg/NOS/NO pathway in vitro and in vivo, and the K_ATP channel could be involved in the regulatory mechanism of H₂S.