Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ß-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.

miR-133a-3p attenuates cardiomyocyte hypertrophy through inhibiting pyroptosis activation by targeting IKKε.

OBJECTIVE: Cardiac hypertrophy is an adaptive response to physiological and pathological stimuli, the latter of which frequently progresses to valvulopathy, heart failure and sudden death. Recent reports revealed that pyroptosis is involved in regulating multiple cardiovascular diseases progression, including cardiac hypertrophy. However, the underlying mechanisms remain poorly understood. This study aims to extensively investigate the regulation of miR-133a-3p on pyroptosis in angiotensin II (Ang II)-induced cardiac hypertrophyin vitro. METHODS: The in vitro model of cardiac hypertrophy was induced by Ang II, which was validated by qPCR combined with measurement of cell surface area by immunofluorescence assay. CCK-8 assay and Hochest33342/PI staining was performed to assess pyroptosis. Dual luciferase reporter system was used to verify the direct interaction between miR-133a-3p and IKKε. The effects of miR-133a-3p/IKKε on pyroptosis activation and cardiac hypertrophy markers (Caspase-1, NLRP3, IL-1ß, IL-18, GSDMD, ASC, ANP, BNP and ß-MHC) were evaluated by western blot, ELISA and qPCR. RESULTS: Ang II treatment could induce cardiomyocyte hypertrophy and pyroptosis. The expression of miR-133a-3p was repressed in Ang II-treated HCM cells, and its overexpression could attenuate both pyroptosis and cardiac hypertrophyin vitro. Additionally, IKKε expression was significantly up-regulated in Ang II-induced HCM cells. Dual luciferase reporter system and qPCR validated that miR-133a-3p directly targeted the 3'-UTR of IKKε and suppressed its expression. Moreover, IKKε overexpression impaired the protective function of miR-133a-3p in cardiomyocyte hypertrophy. CONCLUSION: Collectively, miR-133a-3p attenuates Ang II induced cardiomyocyte hypertrophy via inhibition of pyroptosis by targeting IKKε. Therefore, miR-133a-3p up-regulation may be a promising strategy for cardiac hypertrophy treatment.

Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis.

Irisin, a myokine, is cleaved from the extracellular portion of fibronectin domain-containing 5 protein in skeletal muscle and myocardium and secreted into circulation as a hormone during exercise. Irisin has been found to exert protective effects against lung and heart injuries. However, whether irisin influences myocardial infarction (MI) remains unclear. In this study we investigated the therapeutic effects of irisin in an acute MI model and its underlying mechanisms. Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery and treated with irisin for 2 weeks after MI. Cardiac function was assessed using echocardiography. We found that irisin administration significantly alleviated MI-induced cardiac dysfunction and ventricular dilation at 4 weeks post-MI. Irisin significantly reduced infarct size and fibrosis in post-MI hearts. Irisin administration significantly increased angiogenesis in the infarct border zone and decreased cardiomyocyte apoptosis, but did not influence cardiomyocyte proliferation. In human umbilical vein endothelial cells (HUVEC), irisin significantly increased the phosphorylation of ERK, and promoted the migration of HUVEC detected in wound-healing and transwell chamber migration assay. The effects of irisin were blocked by the ERK inhibitor U0126. In conclusion, irisin improves cardiac function and reduces infarct size in post-MI mouse heart. The therapeutic effect is associated with its pro-angiogenic function through activating ERK signaling pathway.

Remote ischemic conditioning for the prevention of contrast-induced acute kidney injury in patients undergoing intravascular contrast administration: a meta-analysis and trial sequential analysis of 16 randomized controlled trials.

OBJECTIVE: We conducted this meta-analysis to examine the effect of remote ischemic conditioning (RIC) on contrast-induced acute kidney injury (CI-AKI) in patients undergoing intravascular contrast administrationon. METHODS: Pubmed, Embase, and Cochrane Library were comprehensively searched to identify all eligible studies by 15th March, 2017. Risk ratio (RR) and weighted mean difference with the corresponding 95% confidence intervals (CI) were used to examine the treatment effect. The heterogeneity and statistical significance were assessed with Q-test and Z-test, respectively. RESULTS: A total of 16 RCTs including 2175 patients were eventually analyzed. Compared with the control group, RIC could significantly decrease the incidence of CI-AKI (RR=0.58; 95% CI: 0.46, 0.74; P < 0.001), which was further confirmed by the trial sequential analysis. Subgroup analyses showed that remote ischemic preconditioning (RIPrC) and remote ischemic postconditioning (RIPoC) were both obviously effective, and perioperative hydration might enhance the efficiency of RIC. RIC also significantly reduced the major adverse cardiovascular events within six months. CONCLUSION: RIC, whether RIPrC or RIPoC, could effectively exert renoprotective role in intravascular contrast administration and reduce the incidence of relevant adverse events.

Combined effects of TGFB1 +869 T/C and +915 G/C polymorphisms on acute rejection risk in solid organ transplant recipients: a systematic review and meta-analysis.

BACKGROUND: Transforming growth factor-beta 1(TGF-ß1) is involved in the development of acute rejection (AR) episodes in solid organ transplant recipients; and a number of studies have been conducted to investigate the combined effects of human TGF-ß1 gene (TGFB1) +869 T/C and +915 G/C polymorphisms on AR risk. However, the results obtained are inconclusive. METHODS: Eligible studies that investigated the haplotypic association between TGFB1 +869 T/C and +915 G/C polymorphisms and AR risk were comprehensively searched in the PUBMED, EMBASE, China National Knowledge Infrastructure, and Wanfang Database. Statistical analyses were performed by using STATA 12.0 and Review Manager 5.0. RESULTS: Fourteen eligible studies with 565 AR cases and 1219 non-AR cases were included. Overall, a significantly decreased risk was detected in patients carried with intermediate producer (IP) haplotypes (T/C G/C, T/T G/C, and C/C G/G) and/or low producer (LP) haplotypes (C/C G/C, C/C C/C, T/T C/C, and T/C C/C) compared with high producer (HP) haplotypes (T/T G/G and T/C G/G; IP vs. HP: OR = 0.75, 95% CI, 0.58-0.96, P heterogeneity  = 0.238; IP/LP vs. HP: OR  = 0.77, 95% CI, 0.61-0.98, P heterogeneity  = 0.144). In addition, subgroup analysis by transplant types demonstrated a similar association in patients receiving heart transplant (IP vs. HP: OR  = 0.32, 95% CI, 0.14-0.73, P heterogeneity  = 0.790; IP/LP vs. HP: OR  = 0.41, 95% CI, 0.20-0.85, P heterogeneity  = 0.320). CONCLUSIONS: The current meta-analysis and systematic review indicated that recipient TGFB1 HP haplotypes were significantly associated with an increased risk for AR in solid organ transplant recipients, particularly patients receiving cardiac allograft.

Association between transforming growth factor beta-1 +869T/C polymorphism and acute rejection of solid organ allograft: A meta-analysis and systematic review.

BACKGROUND: Transforming growth factor beta-1(TGFB1) is involved in the acute rejection (AR) episodes of solid organ transplant recipients. However, results from published studies on the association between donor/recipient TGFB1 +869T/C polymorphism and AR risk are conflicting and inconclusive. METHODS: PUBMED, EMBASE, CNKI and Wanfang Database were searched to identify eligible studies investigating the association between donor/recipient TGFB1 +869T/C polymorphism and AR risk. Statistical analysis was performed by using STATA 10.0. RESULTS: A total of 29 studies were included. Overall, the donor TGFB1 +869T/C polymorphism was significantly associated with AR risk in heterozygote comparison (CT vs. TT: OR = 1.67, 95%CI, 1.17-2.39; P heterogeneity=0.285) and dominant model (CC vs. TC/TT: OR = 1.47, 95%CI, 1.05-2.06; P heterogeneity=0.445). In addition, subgroup analysis revealed that CT variant (CT vs. TT: OR = 1.97, 95%CI, 1.20-3.25; P heterogeneity = 0.777) and CC/CT genotype (CC/CT vs. TT: OR = 1.72, 95%CI, 1.07, 2.78; P heterogeneity = 0.619) within donors contributed to higher risk of AR in recipients administrated with CsA or FK506, compared with those applied only CsA. On the other hand, no significant association between recipient TGFB1 +869T/C polymorphism and AR was detected in all genetic models. CONCLUSIONS: This meta-analysis and systematic review suggested that donor TGFB1 +869T/C polymorphism was significantly associated with AR of solid organ transplant recipients, and especially among patients in CsA/FK 506 group compared with those in CsA group.

[Expression and localization of vascular endothelial growth factor in the radial artery of the coronary artery bypass grafting patients with diabetes].

OBJECTIVE: To evaluate the quality of the radial artery for coronary artery bypass grafting (CABG) from patients with diabetes by observing the morphology of the radial artery and detecting the expression of vascular endothelial growth factor (VEGF) which may attribute to the long-term patency rate of the coronary artery bypass grafting. METHODS: Samples from 20 cases of diabetic and non-diabetic patients were prospective collected from June 2009 to December 2010. HE staining technique was used to test the morphology of radial artery through the observation of 20 cases of diabetic and 20 cases of non-diabetic patients who undergone CABG. The intimal thicken of the radial artery in the two groups of patients was compared. Western blot and immunofluorescence were then used to test the expression and location of VEGF in the two groups of patients. RESULTS: The radial artery endothelial thickening index and intima/media ratio were significantly higher in the diabetic patients when compared with non-diabetic patients (0.90 ± 0.28 vs. 0.29 ± 0.25, t = 7.27, P < 0.01; 0.90 ± 0.21 vs. 0.37 ± 0.18, t = 8.57, P < 0.01). The expression of VEGF in diabetic patients was significantly higher than non-diabetic patients as revealed by Western blot (1.20 ± 0.21 vs. 0.67 ± 0.15, t = 6.49, P < 0.01). Immunofluorescence showed that VEGF distributed in the cytoplasm of the endothelial cells of diabetic patients radial artery. CONCLUSIONS: Diabetic patient's radial artery intimal thickness is significantly higher than non-diabetic patient's. VEGF may be an important inflammatory cytokine which is leading the radial artery intima thickening in the diabetic patients. The choice of the radial artery grafts in diabetic patients for CABG should be careful.