Explore the vast range of titles available.

Hypoxia/reoxygenation (H/R) is one of the cellular stresses in pathological conditions, such as myocardial infarction, stroke and organ transplantation. Oxidative stress caused by reactive oxygen species (ROS) is a crucial element of H/R injury in vascular endothelial cells (ECs). Xanthine oxidase (XO) has been recognized to contribute to H/R injury. Of note, xanthine oxidoreductase is synthesized as xanthine dehydrogenase (XDH) and needs to be converted to XO to become a source of superoxide. Hepatocyte growth factor (HGF) has been found to protect ECs against H/R injury. The relation, however, between HGF and XO in ECs under H/R conditions remains to be determined. Primary cultured rat cardiac microvascular endothelial cells (CMECs) were exposed to 4 h of hypoxia and followed by 1 h of reoxygenation. Generation of ROS and cytosolic Ca 2+ concentration was measured by flow cytometry qualification of DCFHDA and fluo-3 AM staining cells, respectively. XDH mRNA was qualified by qRT-PCR analysis. XO activity was determined by colorimetric assay and XO protein levels were determined by Western blot. Cell apoptosis was assessed by caspase-3 activity and Annexin V/PI staining. After H/R, cellular ROS production significantly increased. Both XO activity and XO protein increased after H/R. Cellular ROS elevation was inhibited by allopurinol (a potent XO inhibitor), indicting XO accounting for the generation of ROS after H/R. In addition, XDH mRNA increased after H/R, indicating a de novo XDH synthesis, which needs to be converted to XO to become a source of superoxide. Pretreatment of HGF inhibited the elevation of XO activity and XO protein level after H/R; however, HGF has no effect on the increase of XDH mRNA. We also find an increase of the cytosolic Ca 2+ in CMECs after H/R. BAPTA-AM, a cell-permeable Ca 2+ chelator, prevented the increase of XO activity and XO protein levels, implicating the elevated cytosolic Ca 2+ concentration involvement in XO conversion and XO activation. HGF inhibited the elevation of cytosolic Ca 2+ concentration in CMECs after H/R. Furthermore, HGF ameliorated H/R-induced CMECs apoptosis. These findings suggest a novel mechanism whereby HGF inhibited XO-generated ROS production after H/R treatment. H/R induces a de novo synthesis of XDH, the XO precursor. In addition, H/R increases cytosolic Ca 2+ concentration and promotes a Ca 2+ -involved XO conversion and XO activation. HGF has no effect on the increase of XDH mRNA; however, HGF inhibited the elevation of XO protein level and XO activity after H/R in the post-transcriptional level primarily by inhibiting the increase of cytosolic Ca 2+ concentration. HGF protects CMECs from H/R-induced apoptosis by inhibiting the elevation of XO protein level and XO activity.

Background Cancer and coronary artery disease (CAD) is reported to often co-exist in same individuals, however, whether cancer is directly associated with anatomical severity of CAD is rarely studied. The present study aimed to observe the relationship between newly diagnosed cancer and anatomical severity of CAD, moreover, to investigate effect of inflammation on the relationship of cancer with CAD. Methods 374 patients with newly diagnosed cancer who underwent coronary angiography (CAG) were enrolled. Through 1:3 propensity score matching (PSM) to cancer patients based on the age and gender among 51,106 non-cancer patients who underwent CAG, 1122 non-cancer patients were selected as control patients. Anatomical severity of CAD was assessed using SYNTAX score (SXscore) based on coronary angiographic image. SXscore ≤ 22 (highest quartile) was defined as SX-low, and SXscore > 22 as SX-high. The ratio of neutrophil to lymphocyte count (NLR) was used to describe inflammation level. Association between cancer and the anatomical severity of CAD was investigated using logistic regression. Results Univariate logistic regression analysis showed a correlation between cancer and anatomical severity of CAD (OR: 1.419, 95% CI: 1.083–1.859; P  = 0.011). Cancer was associated with increased risk of SX-high after adjusted for common risk factors of CAD (OR: 1.598, 95% CI: 1.172–2.179, P  = 0.003). Significant association between cancer and SX-high was revealed among patients with high inflammation (OR: 1.656, 95% CI: 1.099–2.497, P  = 0.016), but not among patients with low inflammation (OR: 1.530, 95% CI: 0.973–2.498, P  = 0.089). Conclusions Cancer was associated with severity of CAD, however, the association between the two diseases was significant among patients with high inflammation rather than among patients with low inflammation.

Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.

BackgroundMitochondrial fission has been identified as the pathogenesis underlying the development of cardiac microvascular ischemia reperfusion (IR) injury, although the regulatory signaling upstream from fission is far from clear. Bax inhibitor is a novel anti-apoptotic factor, and, however, its role of cardiac microvascular IR injury and mitochondrial homeostasis remains unclear.MethodsThe cardiac microvascular IR injury was performed in WT mice and BI1 transgenic (BITG) mice. The alterations of microvascular structure and function were detected via electron microscope, immunohistochemistry and immunofluorescence in vivo. Cardiac microvascular endothelial cells were isolated form WT and BITG mice and underwent hypoxia/reoxygenation injury in vitro. Cellular viability and apoptosis were analyzed via MTT assay and caspase-3 activity. Mitochondrial function, morphology and apoptosis were detected. Signaling pathways were analyzed via inhibitor, siRNA and mutant plasmid.ResultsHerein, we demonstrated that Bax inhibitor 1 (BI1) was downregulated following cardiac microvascular IR injury, and its expression correlated negatively with microvascular collapse, endothelial cell apoptosis and mitochondrial damage. However, compared to wild-type mice, BI1 transgenic mice were actually protected from the acute microvascular injury and mitochondrial dysfunction. Functional studies illustrated that reintroduced BI1 directly interacted with and inhibited the Syk pathway, leading to the inactivation of Nox2. Subsequently, less Nox2 was associated with ROS downregulation, inhibiting Drp1 phosphorylated activation. Through repression of the Syk–Nox2–Drp1 signaling axis, BI1 strongly disrupted mitochondrial fission, abolishing mitochondrial apoptosis and thus sustaining endothelial cell viability.ConclusionsIn summary, our report illustrates that BI1 functions as a novel microvascular guardian in cardiac IR injury that operates via inhibition of the Syk–Nox2–Drp1-mitochondrial fission signaling axis. Thus, novel therapeutic strategies to regulate the balance between BI1 and mitochondrial fission could provide a survival advantage to microvasculature following IR stress.

Atherosclerosis (AS), a leading cause of cardiovascular disease (CVD), is closely associated with excessive oxidative stress. Dietary nitrate has emerged as a promising intervention for cardiovascular protection through the nitrate-nitrite-nitric oxide (NO) pathway. Meanwhile, dental pulp stem cell (DPSC) possess potent antioxidant properties. However, the potential synergistic effect of sodium nitrate (NaNO ) and DPSC on AS remains unclear. In this study, ApoE mice were fed a high-fat diet (HFD) and treated with NaNO and/or DPSC. The combined treatment markedly attenuated atherosclerotic plaque formation, reduced oxidative stress, increased endothelial NO synthase (eNOS) expression, and decreased circulating monocyte levels. Furthermore, in vitro assays revealed that NaNO and DPSC synergistically alleviated oxidative stress and promoted macrophage polarization toward the M2 phenotype, thereby suppressing oxidized lipid uptake. Mechanistic studies revealed that these benefits were mediated by activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the subsequent upregulation of heme oxygenase-1 (HO-1). Collectively, our findings unveil a novel therapeutic strategy that combines NaNO with DPSC to alleviate oxidative stress and inflammation, presenting a promising approach for the treatment of AS.

Background Clinical studies have shown that atherosclerotic cardiovascular disease and cancer often co‐exist in the same individual. The present study aimed to investigate the role of high‐fat‐diet (HFD)‐induced obesity in the coexistence of the two diseases and the underlying mechanism in apolipoprotein E‐knockout (ApoE−/−) mice. Methods Male ApoE−/− mice were fed with a HFD or a normal diet (ND) for 15 weeks. On the first day of Week 13, the mice were inoculated subcutaneously in the right axilla with Lewis lung cancer cells. At Weeks 12 and 15, serum lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) and vascular endothelial growth factor levels were measured by enzyme‐linked immunosorbent assay, and blood monocytes and macrophages were measured by fluorescence‐activated cell sorting. At Week 15, the volume and weight of the local subcutaneous lung cancer and metastatic lung cancer and the amount of aortic atherosclerosis were measured. Results At Week 15, compared with mice in the ND group, those in the HFD group had a larger volume of local subcutaneous cancer (p = 0.0004), heavier tumors (p = 0.0235), more metastatic cancer in the lungs (p < 0.0001), a larger area of lung involved in metastatic cancer (p = 0.0031), and larger areas of atherosclerosis in the aorta (p < 0.0001). At Week 12, serum LOX‐1, serum vascular endothelial growth factor, and proportions of blood monocytes and macrophages were significantly higher in the HFD group than those in the ND group (p = 0.0002, p = 0.0029, p = 0.0480, and p = 0.0106, respectively); this trend persisted until Week 15 (p = 0.0014, p = 0.0012, p = 0.0001, and p = 0.0204). Conclusions In this study, HFD‐induced obesity could simultaneously promote progression of lung cancer and atherosclerosis in the same mouse. HFD‐induced upregulation of LOX‐1 may play an important role in the simultaneous progression of these two conditions via the inflammatory response and VEGF. Clinical studies showed that atherosclerotic cardiovascular disease (ASCVD) and cancer often coexist in the same individual. The study first showed that obesity could promote atherosclerosis burden as well as promote tumorigenesis and metastasis of lung cancer in the same individual mice. The results showed that obesity could contribute to the coexistence of atherosclerosis and lung cancer; so, screening both ASCVD and lung cancer would be significant in obese patients. LOX‐1‐related pathway likely was a significant contributor to the coexistence of atherosclerosis and lung cancer in the same individual. LOX‐1 could be a target for the management of ASCVD and lung cancer in obese patients.

Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.

Diabetes mellitus (DM), which is a chronic metabolic disorder, is the primary risk factor of life-threatening vascular complications. Endothelial apoptosis is important in the development of the initial vascular lesion preceding the diabetic disease. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor and extensively used in the clinical treatment of DM. DPP-4 inhibitors have been demonstrated to be beneficial in the improvement of endothelial homeostasis, however the molecular mechanism by which they exhibit these effects remains to be elucidated. The effect of sitagliptin on endothelial apoptosis was examined in cultured human umbilical vein endothelial cells (HUVECs) incubated with high glucose (HG). The present study demonstrated that treatment of HUVECs with HG increased reactive oxygen species (ROS) production, stimulated mitochondrial depolarization and resulted in cell apoptosis. Pretreatment of HUVECs with sitagliptin significantly prevented HG-induced endothelial apoptosis. It was further demonstrated that sitagliptin effectively inhibited ROS generation and mitochondrial membrane potential collapse. Similarly, adenosine monophosphate-activated protein kinase (AMPK) activation by sitagliptin protected against HG-induced ROS production, mitochondrial membrane potential collapse and endothelial cell apoptosis, as detected via western blotting and flow cytometry analysis. The present study therefore revealed a novel mechanism of sitagliptin-mediated AMPK activation in preventing endothelial apoptosis and indicated the therapeutic potential of sitagliptin in vascular complications associated with endothelial apoptosis.