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Simple Summary: Fibrosis can affect almost every organ and represents an increasing cause of morbidity and mortality worldwide. Despite significant progress in our understanding of the pathobiology of fibrosis, there is still a lack of putative anti-fibrotic targets to be exploited in anti-fibrosis therapies or used as biomarkers of fibrosis progression. The discovery that HIPK2 can control molecular pathways involved in fibrosis has opened a new field of study in both pathophysiology and the treatment of fibrosis. Fibrosis is an unmet medical problem due to a lack of evident biomarkers to help develop efficient targeted therapies. Fibrosis can affect almost every organ and eventually induce organ failure. Homeodomain-interacting protein kinase 2 (HIPK2) is a protein kinase that controls several molecular pathways involved in cell death and development and it has been extensively studied, mainly in the cancer biology field. Recently, a role for HIPK2 has been highlighted in tissue fibrosis. Thus, HIPK2 regulates several pro-fibrotic pathways such as Wnt/β-catenin, TGF-β and Notch involved in renal, pulmonary, liver and cardiac fibrosis. These findings suggest a wider role for HIPK2 in tissue physiopathology and highlight HIPK2 as a promising target for therapeutic purposes in fibrosis. Here, we will summarize the recent studies showing the involvement of HIPK2 as a novel regulator of fibrosis. [ABSTRACT FROM AUTHOR]

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. Conclusion We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme. [ABSTRACT FROM AUTHOR]

Selenium (Se) is considered to have antioxidant properties, which are beneficial for heart condition. Hyperhomocysteinemia (HHCY) has been suggested to potentially lead to heart failure and is characterized by cardiac fibrosis; however, investigation on the role of Se and HHCY in cardiac fibrosis is rare. Since previous studies demonstrated the important role of the long non-coding RNA maternally expressed 3 (MEG3) in some heart diseases, the present study aimed to determine how Se and MEG3 might exert regulatory effects on HCY-induced fibrosis in cardiac fibroblasts (CFs). Mouse CFs were isolated and treated with HCY and Se. The expression of α-smooth muscle actin (α-SMA), collagen I and III was detected by western blotting to reflect CF fibrosis. Reverse transcription-quantitative PCR was performed to determine the expression levels of MEG3. Inflammation and oxidative stress responses were analyzed by measuring TNF-α, IL-1β (ELISA) and reactive oxygen species levels (using a commercial kit), respectively. Cell Counting Kit-8 was used to evaluate CF proliferation. Total and phosphorylated (p) expression of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) was evaluated by western blotting. CFs were transfected with adenovirus expressing MEG3 short-hairpin RNA to knock down MEG3 expression. Se treatment downregulated the expression level of MEG3 in HCY-stimulated CFs, whilst inhibiting the inflammatory and oxidative stress response. Furthermore, Se inhibited the increased proliferation of CFs following HCY treatment. In addition, MEG3-knockdown in CFs could improve fibrosis caused by HCY. Furthermore, the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 were decreased following treatment with Se or MEG3 silencing. Taken together, the findings from the present study suggested that Se may alleviate cardiac fibrosis by downregulating the expression of MEG3 and reducing the inflammatory and oxidative stress response in CFs. This suggests that Se may be a potential therapeutic option for treating cardiac fibrosis in the future. [ABSTRACT FROM AUTHOR]

The abnormal proliferation and differentiation of cardiac fibroblasts (CFs) are universally regarded as the key process for the progressive development of cardiac fibrosis following various cardiovascular diseases. Huoxin Pill (Concentrated pill, HXP) is a Chinese herbal formula for treating coronary heart disease. However, the cellular and molecular mechanisms of HXP in the treatment of myocardial fibrosis are still unclear. To investigate the effects of HXP on CFs transdifferentiation and collagen synthesis under isoproterenol (ISO) conditions, as well as the potential mechanism of action. In vivo , we established a rat model of cardiac fibrosis induced by ISO, and administered with low or high dose of HXP (10 mg/kg/day or 30 mg/kg/day). The level of α-SMA was detected by immunohistochemistry examination, and combined with RNA-sequencing analysis to determine the protective effect of HXP on myocardial fibrosis rats. In vitro , by culturing primary rat CFs, we examined the effects of HXP on the proliferation and transdifferentiation of CFs using CCK8, scratch wound healing and immunofluorescence assays. Western blot was used to determine protein expression. The findings revealed that HXP protects against ISO-induced cardiac fibrosis and CFs transdifferentiation in rats. RNA-sequencing and pathway analyses demonstrated 238 or 295 differentially expressed genes (DEGs) and multiple enriched signal pathways, including transforming growth factor-beta (TGF-β) receptor signaling activates Smads, downregulation of TGF-β receptor signaling, signaling by TGF-β receptor complex, and collagen formation under treatment with low or high-dose of HXP. Moreover, HXP also markedly inhibited ISO-induced primary rat CFs proliferation, transdifferentiation, collagen synthesis and the upregulation of TGF-β1 and phosphorylated Smad2/3 protein expression. HXP suppresses ISO-induced CFs transdifferentiation and collagen synthesis, and it may exert these effects in part by inhibiting the activation of the TGF-β/Smads pathway. This may be a new therapeutic tool for cardiac fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]