Elevated circulating concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) were found in patients with type 2 diabetes mellitus (T2DM). However, whether a high level of TMAO is related to the risk of diabetes has not been studied. We aimed to synthesize the evidence on the relation between TMAO levels and the risk of diabetes mellitus (DM) and to investigate the association further in a dose-response meta-analysis. PubMed, Web of Science, and Scopus databases were searched for studies from inception to June 2018. A total of 12 clinical studies were included in this study, and 15 314 enrolled subjects were included. A meta-analysis of two-class variables and continuous variables were used to obtain pooled effects. Dose-response meta-analysis was used to investigate the dose-response relationship between TMAO concentrations and the risk of DM.Meta-regression and subgroup analyses were applied to identify the source of heterogeneity in this study. High levels of circulating TMAO were associated with an increased risk of DM (odds ratio [OR] = 1.89) using the two-class meta-analysis.Plasma levels of TMAO in patients with diabetes were higher than in subjects without diabetes (standardized mean difference [SMD]: 0.36) using a meta-analysis of continuous variables. The OR for DM prevalence increased by 54% per 5 μmol L −1 increment of plasma TMAO (OR = 1.54) according to the dose-response metaanalysis. This is the first systematic review and meta-analysis to demonstrate a positive dose-dependent association between circulating TMAO levels and increased diabetes risk.

The gut microbial metabolite trimethylamine N-oxide (TMAO) is increasingly regarded as a novel risk factor for cardiovascular events and mortality. However, little is known about the association between TMAO and hypertension. This meta-analysis was conducted to quantitatively assess the relation between the circulating TMAO concentration and hypertension prevalence. The PubMed, Cochrane Library, and Embase databases were systematically searched up to 17 June 2018. Studies recording the hypertension prevalence in members of a given population and their circulating TMAO concentrations were included. A total of 8 studies with 11,750 individuals and 6176 hypertensive cases were included in the analytic synthesis. Compared with low circulating TMAO concentrations, high TMAO concentrations were correlated with a higher prevalence of hypertension (RR: 1.12; 95% CI: 1.06, 1.17; P < 0.0001; I2 = 64%; P-heterogeneity = 0.007; random-effects model). Consistent results were obtained in all examined subgroups as well as in the sensitivity analysis. The RR for hypertension prevalence increased by 9% per 5-μmol/L increment (RR: 1.09; 95% CI: 1.05, 1.14; P < 0.0001) and 20% per 10-μmol/L increment of circulating TMAO concentration (RR: 1.20; 95% CI: 1.11, 1.30; P < 0.0001) according to the dose–response meta-analysis. To our knowledge, this is the first systematic review and meta-analysis demonstrating a significant positive dose-dependent association between circulating TMAO concentrations and hypertension risk.

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Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear. Approach and Results: We identified a VSMC-enriched lncRNA cardiac mesoderm enhancer-associated noncoding RNA (CARMN) that is dynamically regulated with progression of atherosclerosis. In both mouse and human atherosclerotic plaques, CARMN colocalized with VSMCs and was expressed in the nucleus. Knockdown of CARMN using antisense oligonucleotides in Ldlr −/− mice significantly reduced atherosclerotic lesion formation by 38% and suppressed VSMCs proliferation by 45% without affecting apoptosis. In vitro CARMN gain- and loss-of-function studies verified effects on VSMC proliferation, migration, and differentiation. TGF-β1 (transforming growth factor-beta) induced CARMN expression in a Smad2/3-dependent manner. CARMN regulated VSMC plasticity independent of the miR143/145 cluster, which is located in close proximity to the CARMN locus. Mechanistically, lncRNA pulldown in combination with mass spectrometry analysis showed that the nuclear-localized CARMN interacted with SRF (serum response factor) through a specific 600–1197 nucleotide domain. CARMN enhanced SRF occupancy on the promoter regions of its downstream VSMC targets. Finally, knockdown of SRF abolished the regulatory role of CARMN in VSMC plasticity. Conclusions: The lncRNA CARMN is a critical regulator of VSMC plasticity and atherosclerosis. These findings highlight the role of a lncRNA in SRF-dependent signaling and provide implications for a range of chronic vascular occlusive disease states.

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The exogenous H S donor GYY4137 compensated for the reduced endogenous H S postmucosal wound generation and inhibited the induced M1 macrophage activation. Thus, appropriate H S supplementation may aid in controlling inflammation associated with mucosal wounds.

Pulmonary hypertension (PH) due to left heart disease (LHD) is a common condition associated with significant morbidity. It contributes to the elevation of pulmonary vascular resistance and mean pulmonary pressure, eventually leading to heart failure and even mortality. The present study aimed to explore the potential efficacy of late and long-term treatment with a Rho-kinase (ROCK) signaling inhibitor, namely fasudil, in a rat model of end-stage PH-LHD. The PH-LHD model was established by supracoronary aortic banding, and the effect of fasudil treatment on the progression of PH-LHD was monitored. After 9 weeks (63 days) of supracoronary aortic banding, a significant increase in mean pulmonary pressure and RV systolic pressure was observed in the rats, associated with increased RhoA/ROCK activity in the lungs. Therapy with fasudil (30 mg/kg/day, intraperitoneal) for 4 weeks from postoperative day 35 reversed the hemodynamic disorder and prevented pulmonary vascular remodeling in rats with PH-LHD. In addition, the blockade of ROCK signaling by fasudil decreased the protein levels of endothelin-1 (ET-1) and the mRNA expression levels of endothelin A receptor and promoted the production of nitric oxide (NO) in rats with PH-LHD. Furthermore, fasudil inhibited the migration of human pulmonary microvascular endothelial cells and the proliferation of pulmonary artery smooth muscle cells induced by ET-1. Therefore, this late, long-term blockade of the ROCK pathway by fasudil may be a promising strategy to reverse hemodynamic dysfunction and impede the development of end-stage PH-LHD in patients.

Patients with peripheral artery disease (PAD) and diabetes have the highest risk of critical limb ischemia (CLI) and amputation, yet the underlying mechanisms remain incompletely understood. MicroRNA (miRNA)-sequencing of plasma from diabetic patients with or without CLI was compared to diabetic mice with acute or subacute limb ischemia to identify conserved miRNAs. miRNA knockout mice on high fat diet were generated to explore impact on CLI. Comparison of dysregulated miRNAs from diabetic human subjects with PAD and diabetic mice with limb ischemia revealed conserved miR-181 family members. High fat-fed, diabetic Mir181a2b2 knockout (KO) mice had impaired revascularization in limbs due to abrogation of circulating Ly6C hi monocytes with reduced accumulation in ischemic skeletal muscles. M2-like KO macrophages under diabetic conditions failed to produce pro-angiogenic cytokines. Single cell transcriptomics of the bone marrow niche revealed that the reduced monocytosis in diabetic KO mice is a result of impaired hematopoiesis with increased CXCR4 signaling in bone marrow Lineage -Sca1 + Kit + (LSK) cells. Exogenous Ly6C hi monocytes from nondiabetic KO mice rescued the impaired revascularization in ischemic limbs of diabetic KO mice. Increased Cxcr4 expression is mediated by the novel miR-181 target, Plac8.Taken together, MiR-181a/b is a putative mediator of diabetic CLI and contributes to alterations in hematopoiesis, monocytosis, and macrophage polarization.