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Abstract MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a human paracaspase protein with proteolytic activity via its caspase-like domain. The pharmacological inhibition of MALT1 by MI-2, a specific chemical inhibitor, diminishes the response of endothelial cells to inflammatory stimuli. However, it is largely unknown how MALT1 regulates the functions of vascular smooth muscle cells (SMCs). This study aims to investigate the impact of MALT1 inhibition by MI-2 on the functions of vascular SMCs, both in vitro and in vivo. MI-2 treatment led to concentration- and time-dependent cell death of cultured aortic SMCs, which was rescued by the iron chelator deferoxamine (DFO) or ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, but not by inhibitors of apoptosis (Z-VAD-fmk), pyroptosis (Z-YVAD-fmk), or necrosis (Necrostatin-1, Nec-1). MI-2 treatment downregulated the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy polypeptide 1 (FTH1), which was prevented by pre-treatment with DFO or Fer-1. MI-2 treatment also activated autophagy, which was inhibited by Atg7 deficiency or bafilomycin A1 preventing MI-2-induced ferroptosis. MI-2 treatment reduced the cleavage of cylindromatosis (CYLD), a specific substrate of MALT1. Notably, MI-2 treatment led to a rapid loss of contractility in mouse aortas, which was prevented by co-incubation with Fer-1. Moreover, local application of MI-2 significantly reduced carotid neointima lesions and atherosclerosis in C57BL/6J mice and apolipoprotein-E knockout (ApoE−/−) mice, respectively, which were both ameliorated by co-treatment with Fer-1. In conclusion, the present study demonstrated that MALT1 inhibition induces ferroptosis of vascular SMCs, likely contributing to its amelioration of proliferative vascular diseases.

Abstract Background The type and placement of chest tube for patients undergoing uniportal video‐assisted thoracoscopic lobectomy remains controversial. The aim of this study was to assess the efficacy and safety of a novel technique in which a pigtail catheter was used alone as the chest tube and placed near the incision for chest drainage after uniportal video‐assisted thoracoscopic lobectomy and extended lymphadenectomy. Methods A total of 217 patients undergoing uniportal video‐assisted thoracoscopic lobectomy were retrospectively reviewed and divided into two groups. In group A, a 12‐Fr pigtail catheter with several side ports was placed next to the uniportal wound. In group B, a conventional 20‐Fr chest tube was placed through the uniportal wound itself. Postoperative complications related to chest tube placement and patients' subjective satisfaction were compared between the two groups. Postoperative pain management effect and other clinical outcomes such as duration of chest drainage and postoperative stay were also compared. Results There were 112 patients in group A and 105 patients in group B. A significantly lower incidence of wound complications was found in group A postoperatively (p = 0.034). The pain score on coughing in group A was significantly lower than that in group B on postoperative day two (POD2) (p = 0.021). There was no significant difference of other clinical outcomes such as duration of chest drainage and postoperative stay as well as major complications between the two groups. Conclusion Placing a 12‐Fr pigtail catheter alone next to the uniportal wound for chest drainage might be effective and safe after uniportal video‐assisted thoracoscopic lobectomy and extended lymphadenectomy.

Abstract Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti‐hypertensive. Using a meta‐analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002–2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was –1.42 (95% CI: –2.38, –0.46; p = .004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: –1.28, –0.36; p = .0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non‐significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi‐ethnic, large sample pool size, and a long period follow‐up study is still required to assert these claims.

Hydrogen sulfide (H2S), a gas transmitter found in eukaryotic organisms, plays an essential role in several physiological processes. H2S is one of the three primary biological gas transmission signaling mediators, along with nitric oxide and carbon monoxide. Several animal and in vitro experiments have indicated that H2S can prevent coronary endothelial mesenchymal transition, reduce the expression of endothelial cell adhesion molecules, and stabilize intravascular plaques, suggesting its potential role in the treatment of atherosclerosis (AS). H2S donors are compounds that can release H2S under certain circumstances. Development of highly targeted H2S donors is a key imperative as these can allow for in-depth evaluation of the anti-atherosclerotic effects of exogenous H2S. More importantly, identification of an optimal H2S donor is critical for the creation of H2S anti-atherosclerotic prodrugs. In this review, we discuss a wide range of H2S donors with anti-AS potential along with their respective transport pathways and design-related limitations. We also discuss the utilization of nano-synthetic technologies to manufacture H2S donors. This innovative and effective design example sheds new light on the production of highly targeted H2S donors.

(+)-JQ1, a specific chemical inhibitor of bromodomain and extraterminal (BET) family protein 4 (BRD4), has been reported to inhibit smooth muscle cell (SMC) proliferation and mouse neointima formation via BRD4 regulation and modulate endothelial nitric oxide synthase (eNOS) activity. This study aimed to investigate the effects of (+)-JQ1 on smooth muscle contractility and the underlying mechanisms. Using wire myography, we discovered that (+)-JQ1 inhibited contractile responses in mouse aortas with or without functional endothelium, reducing myosin light chain 20 (LC20) phosphorylation and relying on extracellular Ca2+. In mouse aortas lacking functional endothelium, BRD4 knockout did not alter the inhibition of contractile responses by (+)-JQ1. In primary cultured SMCs, (+)-JQ1 inhibited Ca2+ influx. In aortas with intact endothelium, (+)-JQ1 inhibition of contractile responses was reversed by NOS inhibition (L-NAME) or guanylyl cyclase inhibition (ODQ) and by blocking the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. In cultured human umbilical vein endothelial cells (HUVECs), (+)-JQ1 rapidly activated AKT and eNOS, which was reversed by PI3K or ATK inhibition. Intraperitoneal injection of (+)-JQ1 reduced mouse systolic blood pressure, an effect blocked by co-treatment with L-NAME. Interestingly, (+)-JQ1 inhibition of aortic contractility and its activation of eNOS and AKT were mimicked by the (−)-JQ1 enantiomer, which is structurally incapable of inhibiting BET bromodomains. In summary, our data suggest that (+)-JQ1 directly inhibits smooth muscle contractility and indirectly activates the PI3K/AKT/eNOS cascade in endothelial cells; however, these effects appear unrelated to BET inhibition. We conclude that (+)-JQ1 exhibits an off-target effect on vascular contractility.

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-β-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

Abstract Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis.

Background/Aims: Our recent data indicated that Mipu1 overexpression reduces lipid intake and CD36 expression of macrophages in the presence of oxLDL. However, the mechanism of Mipu1 inhibiting lipid accumulation in macrophages is not elucidated. Methods: Real-time quantitative polymerase chain reaction (PCR) and western blot analysis were used to detect expression of Mipu1 and CD36. The promoter activity of CD36 was studied using luciferase assays. Chromatin immunoprecipitation (ChIP) was used to show the recruitment of Mipu1 onto the CD36 promoter. High-performance liquid chromatography and Dil-labeled lipoprotein were used to detect cholesterol accumulation. Results: Here, we show that CD36 overexpression rescues oxLDL-induced cholesterol accumulation in RAW264.7-Mipu1 cells. Analysis of the mouse CD36 promoter revealed two potential Mipu1-response elements (MRE), one of which (from -237bp to -244bp, ACTTAC) was shown, using mutagenesis and deletion analysis, to be functional. Mipu1 was demonstrated to bind to CD36 promoter, and oxLDL treatment resulted in increases in their interaction as assessed by ChIP. Conclusions: It was demonstrated that Mipu1 inhibited the lipid accumulation of macrophages and it down-regulated CD36 expression in the presence of oxLDL.

Ten-eleven translocation-2 (TET2) protein is a DNA demethylase that regulates gene expression through DNA demethylation and also plays important roles in various diseases including atherosclerosis. Endothelial dysfunction represents an early key event in atherosclerotic disease. The cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) is a key endogenous system with protective effects on endothelial functions. In this study, we examined how TET2 regulates oxidized low-density lipoprotein (oxLDL)-induced dysfunction of human umbilical vein endothelial cells (HUVECs) and determined the role of the CSE/H2S system. Treatment with oxLDL resulted in downregulation of both TET2 expression and CSE/H2S system in HUVECs. TET2 was found to have protective effects on oxLDL-induced HUVEC dysfunction, which was confirmed with TET2 overexpression plasmid or TET2 shRNA plasmid. Moreover, TET2 was found to upregulate the CSE/H2S system and inhibit NF-κB activation, leading to decreased expression of ICAM-1 and VCAM-1 and attenuated adhesion of THP-1 cells to oxLDL-activated HUVECs. The protective effect of TET2 was reduced by treatment with CSE siRNA. Further studies revealed that CSE promoter region contains a well-defined CpG island. We also showed that TET2 enhanced 5-hydroxymethylcytosine (5hmC) level and promoted DNA demethylation of CSE gene promoter, leading to an increase in CSE expression. In conclusion, TET2 has protective effects on oxLDL-induced HUVEC dysfunction, likely through upregulating the CSE/H2S system by DNA demethylation of CSE gene promoter. TET2 may become a novel therapeutic target for endothelial dysfunction-associated vascular diseases.