Background: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype and function of so-called tissue Tregs in the heart remain unclear. Methods: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury (I/R injury) or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA-sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or I/R injury. Photoconversion, parabiosis, single-cell TCR sequencing and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin (IL)-33/ST2 axis and secreted acidic cysteine rich glycoprotein (Sparc), a molecule upregulated in heart Tregs, was further evaluated in functional assays. Results: We showed that Tregs were highly enriched in the myocardium of MI, I/R injury and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts compared to their lymphoid counterparts including heart draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly due to recruitment from circulating Treg pool, while local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected TCR of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, Helios high Nrp-1 high phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 + T cells (Tconvs), proved by the analysis of TCR repertoires and Tconvs adoptive transfer experiments. Notably, the IL-33/ST2 axis was essential for sustaining heart Treg populations. Finally, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone. Conclusions: We identified and characterized a phenotypically and functionally unique population of heart Tregs, which may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.

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Recently, the roles of toll like receptor (TLR) gene polymorphisms in atherosclerotic diseases were extensively investigated, with conflicting results. Therefore, we performed this study to better assess the relationship between TLR gene variants and atherosclerosis. Eligible studies were searched in PubMed, MEDLINE, EMBASE, Web of Science and CNKI. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate associations between TLR gene polymorphisms and atherosclerosis. A total of 40 studies covering 19,657 cases and 15,660 controls were finally included in our systematic review and meta-analysis. Significant correlations with atherosclerosis susceptibility were found for the TLR1 rs5743551 polymorphism (dominant model: 95% CI 1.03-1.79; recessive model: 95% CI 0.28-0.97; allele model: 95% CI 1.07-1.69), TLR1 rs5743611 polymorphism (dominant model: 95% CI 0.56-0.98) and TLR6 rs5743810 polymorphism (recessive model: 95% CI 0.56-0.92) in overall analyses. Moreover, further subgroup analyses revealed that TLR4 rs1927911 polymorphism was significantly associated with the risk of cerebral infarction in the recessive model (95% CI 0.46-0.96), whereas TLR4 rs4986791 polymorphism was significantly correlated with susceptibility to atherosclerosis among Asians in the dominant (95% CI 1.58-6.66), additive (95% CI 0.13-0.69) and allele (95% CI 1.58-5.53) models. However, no positive results were found for the other 13 TLR polymorphisms. In conclusion, our findings indicate that most TLR gene polymorphisms may not be implicated in the pathogenesis of atherosclerosis, whereas certain TLR gene variations, such as rs5743551, rs5743611, rs5743810, rs4986791 and rs1927911, may serve as genetic biomarkers of atherosclerotic diseases.

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This systematic review and meta-analysis aimed to better elucidate the roles of genetic factors in Kawasaki disease (KD), and determine the potential genetic biomarkers of KD. The systematic literature search of PubMed, Medline, Embase, Web of Science and CNKI identified 164 eligible studies. The qualitative synthesis revealed that 62 genes may be correlated with the susceptibility to KD, and 47 genes may be associated with the incidence of coronary artery lesions (CALs) in KD. A total of 53 polymorphisms in 34 genes were investigated in further quantitative synthesis. Of these, 23 gene polymorphisms were found to be significantly correlated with KD susceptibility, and 10 gene polymorphisms were found to be significantly associated with the incidence of CALs in KD. In conclusion, our findings indicate that gene polymorphisms of ACE, BLK, CASP3, CD40, FCGR2A, FGβ, HLA-E, IL1A, IL6, ITPKC, LTA, MPO, PD1, SMAD3, CCL17 and TNF may affect KD susceptibility. Besides, genetic variations in BTNL2, CASP3, FCGR2A, FGF23, FGβ, GRIN3A, HLA-E, IL10, ITPKC and TGFBR2 may serve as biomarkers of CALs in KD.

Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD. We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD. Nrg4 levels were negatively associated with the SYNTAX score (r = −0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions. Nrg4 levels were found to be inversely associated with the presence and severity of CAD.

BackgroundXuezhikang is the extract of red yeast rice, which has been widely used for the management of atherosclerotic disease, but the molecular basis of its antiatherosclerotic effects has not yet been fully identified. Here we investigated the changes of eNOS in vascular endothelia and RBCs, eNOS regulatory factor Caveolin-1 in endothelia, and hemorheological parameters in atherosclerotic rats to explore the protective effects of Xuezhikang.Methodology/Principal FindingsWistar rats were divided into 4 groups (n = 12/group) group C, controls; group M, high-cholesterol diet (HCD) induced atherosclerotic models; group X, HCD+Xuezhikang; and group L, HCD +Lovastatin. In group X, Xuezhikang inhibited oxidative stress, down-regulated caveolin-1 in aorta wall (P<0.05), up-regulated eNOS expression in vascular endothelia and erythrocytes (P<0.05), increased NOx (nitrite and nitrate) in plasma and cGMP in erythrocyte plasma and aorta wall (P<0.05), increased erythrocyte deformation index (EDI), and decreased whole blood viscosity and plasma viscosity (P<0.05), with the improvement of arterial pathology.Conclusions/SignificanceXuezhikang up-regulated eNOS expression in vascular endothelia and RBCs, increased plasma NOx and improved abnormal hemorheology in high cholesterol diet induced atherosclerotic rats. The elevated eNOS/NO and improved hemorheology may be beneficial to atherosclerotic disease.

China has stepped into an aging society. The social service development statistical bulletin 2015 published in July 2016 by Ministry of Civil Affairs showed that till the end of 2015, the amount of people ≥60 years of age had already approached to 222 million, which comprised 16.1% of the Chinese population, while the amount of people ≥65 years of age comprised 10.5% of the Chinese population was 143 million.1 Hypertension is an independent risk factor for cardio‐cerebral‐vascular diseases and is a primary and contributory cause for death and disability in the elderly. A large number of epidemiological and clinical studies have shown that the risk of target organ damage of hypertension such as ischemic heart disease, cardiac insufficiency, stroke, chronic kidney disease, and aortic and peripheral artery diseases significantly increases with aging. Blood pressure control plays a significant role in reducing cardio‐cerebral‐vascular events and all‐cause mortality.2 Compared to younger patients with similar blood pressure elevation, the risks of cardiovascular and cerebrovascular events significantly increase in the elderly. Because of specialties in the pathogenesis and clinical manifestation in older patients with hypertension, physicians should pay more attention to the population characteristics and individual treatments.