Tudor-SN exacerbates pathological vascular remodeling by promoting the polyubiquitination of PTEN via NEDD4-1.

BACKGROUND: Dysregulation of vascular homeostasis can induce cardiovascular diseases and increase global mortality rates. Although lineage tracing studies have confirmed the pivotal role of modulated vascular smooth muscle cells (VSMCs) in the progression of pathological vascular remodeling, the underlying mechanisms are still unclear. METHODS: The expression of Tudor-SN was determined in VSMCs of artery stenosis, PDGF-BB-treated VSMCs and atherosclerotic plaque. Loss- and gain-of-function approaches were used to explore the role of Tudor-SN in the modulation of VSMCs phenotype both in vivo and in vitro. RESULTS: In this study, we demonstrate that Tudor-SN expression is significantly elevated in injury-induced arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency attenuates, but overexpression aggravates the synthetic phenotypic switching of VSMCs and pathological vascular remodeling. Loss of Tudor-SN also reduces atherosclerotic plaque formation and increases plaque stability. Mechanistically, PTEN, the major regulator of the MAPK and PI3K-AKT signaling pathways, plays a vital role in Tudor-SN-mediated regulation on proliferation and migration of VSMCs. Tudor-SN facilitates the polyubiquitination and degradation of PTEN via NEDD4-1, thus exacerbating vascular remodeling under pathological conditions. BpV (HOpic), a specific inhibitor of PTEN, not only counteracts the protective effect of Tudor-SN deficiency on proliferation and migration of VSMCs, but also abrogates the negative effect of carotid artery injury-induced vascular remodeling in mice. CONCLUSIONS: Our findings reveal that Tudor-SN deficiency significantly ameliorated pathological vascular remodeling by reducing NEDD4-1-dependent PTEN polyubiquitination, suggesting that Tudor-SN may be a novel target for preventing vascular diseases.

PARP1 Promotes Heart Regeneration and Cardiomyocyte Proliferation.

Myocardial infarction causes cardiomyocyte loss, and depleted cardiomyocyte proliferative capacity after birth impinges the heart repair process, eventually leading to heart failure. This study aims to investigate the role of Poly(ADP-Ribose) Polymerase 1 (PARP1) in the regulation of cardiomyocyte proliferation and heart regeneration. Our findings demonstrated that PARP1 knockout impaired cardiomyocyte proliferation, cardiac function, and scar formation, while PARP1 overexpression improved heart regeneration in apical resection-operated mice. Mechanistically, we found that PARP1 interacts with and poly(ADP-ribosyl)ates Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1) and increases binding between HSP90AB1 and Cell Division Cycle 37 (CDC37) and cell cycle kinase activity, thus activating cardiomyocyte cell cycle. Our results reveal that PARP1 promotes heart regeneration and cardiomyocyte proliferation via poly(ADP-ribosyl)ation of HSP90AB1 activating the cardiomyocyte cell cycle, suggesting that PARP1 may be a potential therapeutic target in treating cardiac injury.

Theaflavin-3,3'-Digallate from Black Tea Inhibits Neointima Formation Through Suppression of the PDGFRß Pathway in Vascular Smooth Muscle Cells.

The abnormal neointima formation caused by the phenotypic switching of vascular smooth cells (VSMCs) into a synthetic state plays a key role in the pathogenesis of various vascular diseases, including atherosclerosis and postangioplasty restenosis. Theaflavin-3,3'-digallate (TF3) in black tea has been reported to exert antiinflammatory and anticancer effects, but its role in neointima formation remains unclear. Here, we delineated a remarkable effect of TF3 in suppressing neointima formation of VSMCs in vivo as well as the ability of primary rat aortic smooth cells (RASMCs) to proliferate and migrate in vitro. Further study confirmed that the effects of TF3 on PDGF-BB-induced RASMCs were due to reduced phosphorylation of PDGFRß, which led to the repression of downstream pathways. We concluded that TF3 may act as a repressor in the progression of neointima formation and serve as a potential therapeutic candidate for excessive phenotypic switching of VSMCs.

Daidzein suppresses TGF-ß1-induced cardiac fibroblast activation via the TGF-ß1/SMAD2/3 signaling pathway.

Myocardial fibrosis is a concomitant bioprocess associated with many cardiovascular diseases (CVDs). Daidzein is an isoflavone that has been used for the treatment of CVDs. This study aimed to reveal its role in myocardial fibrosis. Our results indicate that daidzein had a nontoxic effect on cardiac fibroblasts and that TGF-ß1 and TGFßRI levels were gradually decreased by daidzein in a dose-dependent manner. In the current study, we show that daidzein significantly inhibited TGF-ß1-induced mRNA and protein expression of α-SMA, collagen I, and collagen III. Accordingly, immunofluorescence staining of α-SMA was performed. Daidzein also inhibited TGF-ß1-induced cardiac fibroblast proliferation and migration. Mechanistically, daidzein inhibited the TGF-ß/SMAD signaling pathway induced by TGF-ß1 in cardiac fibroblasts. Additionally, daidzein ameliorated MI-induced cardiac dysfunction and cardiac fibrosis in vivo. Based on these findings, we conclude that daidzein reduces TGF-ß1-induced cardiac fibroblast activation by partially regulating the TGF-ß1/SMAD2/3 signaling pathway.