The role of zyxin in signal transduction and its relationship with diseases.

This review highlighted the pivotal role of zyxin, an essential cell focal adhesions protein, in cellular biology and various diseases. Zyxin can orchestrate the restructuring and dynamic alterations of the cellular cytoskeleton, which is involved in cell proliferation, adhesion, motility, and gene transcription. Aberrant zyxin expression is closely correlated with tumor cell activity and cardiac function in both tumorigenesis and cardiovascular diseases. Moreover, in fibrotic and inflammatory conditions, zyxin can modulate cellular functions and inflammatory responses. Therefore, a comprehensive understanding of zyxin is crucial for deciphering signal transduction networks and disease pathogenesis. Investigating its role in diseases holds promise for novel avenues in early diagnosis and therapeutic strategies. Nevertheless, targeting zyxin as a therapeutic focal point presents challenges in terms of specificity, safety, drug delivery, and resistance. Nonetheless, in-depth studies on zyxin and the application of precision medicine could offer new possibilities for personalized treatment modalities.

GSDMD-mediated pyroptosis promotes cardiac remodeling in pressure overload.

BACKGROUND: Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload. METHODS: Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA. RESULTS: We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway. CONCLUSION: In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload.

CXCR6 Mediates Pressure Overload-Induced Aortic Stiffness by Increasing Macrophage Recruitment and Reducing Exosome-miRNA29b.

Aortic stiffness is an independent risk factor for aortic diseases such as aortic dissection which commonly occurred with aging and hypertension. Chemokine receptor CXCR6 is critically involved in vascular inflammation and remodeling. Here, we investigated whether and how CXCR6 plays a role in aortic stiffness caused by pressure overload. CXCR6-/- and WT mice underwent transverse aortic constriction (TAC) surgery for 8 weeks. CXCR6 deficiency significantly improved TAC-induced aortic remodeling and endothelial dysfunction by decreasing CD11c+ macrophage infiltration, suppressing VCAM-1 and ICAM-1, reducing collagen deposition, and downregulating MMP12 and osteopontin in the aorta. Consistently, blocking the CXCL16/CXCR6 axis also reduced aortic accumulation of CD11c+ macrophages and vascular stiffness but without affecting the release of TNF-α and IL-6 from the aorta. Furthermore, pressure overload inhibited aortic release of exosomes, which could be reversed by suppressing CXCR6 or CXCL16. Inhibition of exosome release by GW4869 significantly aggravated TAC-induced aortic calcification and stiffness. By exosomal microRNA microarray analysis, we found that microRNA-29b was significantly reduced in aortic endothelial cells (AECs) receiving TAC. Intriguingly, blocking the CXCL16/CXCR6 axis restored the expression of miR-29b in AECs. Finally, overexpression of miR-29b significantly increased eNOS and reduced MMPs and collagen in AECs. By contrast, antagonizing miR-29b in vivo further enhanced TAC-induced expressions of MMP12 and osteopontin, aggravated aortic fibrosis, calcification, and stiffness. Our study demonstrated a key role of the CXCL16/CXCR6 axis in macrophage recruitment and macrophage-mediated aortic stiffness under pressure overload through an exosome-miRNAs-dependent manner.

Gender Differences in Cardiac Hypertrophy.

Cardiac hypertrophy is an adaptive response to abnormal physiological and pathological stimuli, which can be classified into concentric and eccentric hypertrophy, induced by pressure overload or volume overload, respectively. In both physiological and pathological scenarios, females generally show a more favorable form of hypertrophy compared with their male counterparts. However once established, cardiac hypertrophy is a stronger risk factor for heart failure in females. Pre-menopausal women are better protected against cardiac hypertrophy compared with men, but this protection is abolished following menopause and is partially restored after estrogen replacement therapy. Estrogen exerts its protection by counteracting pro-hypertrophy signaling pathways, whereas androgen mostly plays an opposite role in cardiac hypertrophy. We here summarize the progress in the understanding of sexual dimorphisms in cardiac hypertrophy and highlight recent breakthroughs in the regulatory role of sex hormones and their intricate molecular networks, in order to shed light on gender-oriented therapeutic efficacy for pathological hypertrophy.

Downregulation of MiR-199b-5p Inducing Differentiation of Bone-Marrow Mesenchymal Stem Cells (BMSCs) Toward Cardiomyocyte-Like Cells via HSF1/HSP70 Pathway.

BACKGROUND Bone-marrow mesenchymal stem cells (BMSCs) are pluripotent stem cells with potent self-renewal and differentiation ability that are widely used in transplantation of cell therapy. But the mechanism on microRNA (miRNA) regulating stem cell differentiation is complicated and unclear. The aim of this study was to investigate whether miR-199b-5p is involved in differentiation of cardiomyocyte-like cells and identify potential signal pathways in BMSCs. MATERIAL AND METHODS Mouse BMSCs were treated with 5-azacytidine and transfected by miR-199b-5p mimic and inhibitor, respectively. qRT-PCR was used to detect the expression of miR-199b-5p in BMSCs, 5-azacytidine treated BMSCs, and neonatal murine cardiomyocytes. The expression of cardiac specific genes and the HSF1/HSP70 signal pathway were examined by qRT-PCR or western blotting. The proliferation and migration of BMSCs were evaluated by CCK-8 assay and wound-healing assay. RESULTS The expression of miR-199b-5p decreased gradually in the process of differentiation of BMSCs toward cardiomyocyte-like cells. The expression of cardiac specific genes and HSF1/HSP70 were increased in the miR-199b-5p inhibitor group; however, the miR-199b-5p mimic group presented an opposite result. Both the miR-199b-5p inhibitor group and the miR-199b-5p mimic group had no influence on BMSCs proliferation and migration. Using lentivirus vectors bearing HSF1 shRNA to silence HSF1 and HSP70, the anticipated elevated expression effect of cardiac specific genes induced by miR-199b-5p inhibitor was suppressed. CONCLUSIONS Downregulation of miR-199b-5p induced differentiation of BMSCs toward cardiomyocyte-like cells partly via the HSF1/HSP70 signaling pathway, and had no influence on BMSCs proliferation and migration.

Role of heat shock transcription factor 1(HSF1)-upregulated macrophage in ameliorating pressure overload-induced heart failure in mice.

In order to explore the role of macrophages in HSF1-mediated alleviation of heart failure, mice model of pressure overload-induced heart failure was established using transverse aortic constriction (TAC). Changes in cardiac function and morphology were studied in TAC and SHAM groups using ultrasonic device, tissue staining, electron microscopy, real-time quantitative polymerase chain reaction (RT-QPCR), and Western blotting. We found that mice in the TAC group showed evidence of impaired cardiac function and aggravation of fibrosis on ultrasonic and histopathological examination when compared to those in the SHAM group. The expressions of HSF1, LC3II/LC3I, Becline-1 and HIF-1, as well as autophagosome formation in TAC group were greater than that in SHAM group. On sub-group analyses in the TAC group, improved cardiac function and alleviation of fibrosis was observed in the HSF1 TG subgroup as compared to that in the wild type subgroup. Expressions of LC3II/LC3I, Becline-1 and HIF-1, too showed an obvious increase; and increased autophagosome formation was observed on electron microscopy. Opposite results were observed in the HSF1 KO subgroup. These results collectively suggest that in the pressure overload heart failure model, HSF1 promoted formation of macrophages by inducing upregulation of HIF-1 expression, through which heart failure was ameliorated.

Role of HSF1-upregulated AC6 in ameliorating heart failure in mice.

PURPOSE: Our previous studies discovered that Heat shock factor 1(HSF1) can alleviate pressure overload induced heart failure in mice. However, its molecular mechanisms are yet to be further explained. Many studies have already verified that Adenylyl Cyclase 6 (AC6) can ameliorate heart failure, but it is still unknown whether or not the pathway HSF1 is involved in the process. Our preliminary experiment showed that the expression level of AC6 is positively associated with HSF1. Therefore, in the present study, we aimed to explore whether HSF1 can play its role in ameliorating heart failure by regulating AC6, and how the potential internal mechanisms work. METHODS: We applied the Transverse Aortic Constriction (TAC) for 4 weeks to develop the C57BL/6 mice pressure overload induced heart failure model. First, the mice were divided into TAC group and SHAM group. Changes in the cardiac function and morphology of the mice were observed by an ultrasonic device and Masson staining slices, expressions of AC6 mRNA were observed by RT-QPCR, expressions of HSF1 and proteinkinase A (PKA) were examined by Western Blotting, and the levels of cyclic adenosine monophosphate (cAMP) from aortic blood were measured by ELISA. Second, the TAC group were further divided into subgroups of HSF1 transgene mice, HSF1 knockout mice and wild type mice, followed by the aforesaid observations. RESULTS: In the SHAM group, no obvious variations of cardiac function, AC6 mRNAHSF1, PKA, cAMP and other test results were found among each of the subgroups. Compared to the SHAM group, the TAC group presented clearly weakened heart functions, while, expressions of AC6 mRNA, HSF1, PKA and cAMP all recorded obvious increases. In the TAC group, compared to the WT subgroup, the HSF1 KO subgroup presented decreases in expressions of AC6 mRNA, HSF1, PKA and cAMP, and at the same time, the heart functions were weaker, while, the HSF1 TG subgroup recorded the contrary results. CONCLUSION: In the pressure overload heart failure model, HSF1 can ameliorate heart failure by positively regulating the pathway of AC6/cAMP/PKA.

Association between a vascular endothelial growth factor gene polymorphism (rs2146323) and diabetic retinopathy: a meta-analysis.

BACKGROUND: Vascular endothelial growth factor (VEGF) is thought to play an important role in the pathogenesis of diabetic retinopathy (DR). Previous studies have associated the VEGF rs2146323 polymorphism with the risk of DR. However, the results of these studies are inconsistent. A meta-analysis was performed to evaluate the association between the VEGF rs2146323 polymorphism and the risk of DR. METHODS: The PubMed, EMBASE, Web of Science and Google Scholar literature databases until March 2015 were searched. The differences in the studies were expressed in the form of an odds ratio (OR) and the corresponding 95% confidence interval (CI). Heterogeneity among the studies was tested using the I(2) statistic based on the Q test. RESULTS: A total of four studies (598 cases and 709 controls) were included in the meta-analysis. A significant association was found involving the rs2146323 polymorphism in the dominant model (CA + AA VS. CC) (OR = 1.38, CI = 1.10-1.72, P = 0.005) and the co-dominant model (CA VS. CC) (OR = 1.37, CI = 1.08-1.74, P = 0.008). CONCLUSIONS: Our meta-analysis confirmed the association between the VEGF rs2146323 polymorphism and the risk of DR.