Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Synthesis and evaluation of novel fluorinated hematoporphyrin ether derivatives for photodynamic therapy.

A photosensitizer with high phototoxicity, suitable amphipathy and low dark toxicity could play a pivotal role in photodynamic therapy (PDT). In this study, a facile and versatile approach was adopted to synthesize a series of novel fluorinated hematoporphyrin ether derivatives (I1-I5 and II1-II4), and the photodynamic activities of these compounds were studied. Compared to hematoporphyrin monomethyl ether (HMME), all PSs showed preferable photodynamic activity against A549 lung tumor cells. The longest visible absorption wavelength of these compounds was approximately 622 nm. Among them, II3 revealed the highest singlet oxygen yield (0.0957 min-1), the strongest phototoxicity (IC50 = 1.24 µM), the lowest dark toxicity in vitro, and exhibited excellent anti-tumor effects in vivo. So compound II3 could act as new drug candidate for photodynamic therapy.

Synthesis and evaluation of novel chlorophyll a derivatives as potent photosensitizers for photodynamic therapy.

Chlorophyll a exhibits excellent photosensitive activity in photosynthesis. The unstability limited its application as photoensitizer drug in photodynamic therapy. Here a series of novel chlorophyll a degradation products pyropheophorbide-a derivatives were synthesized and evaluated for lung cancer in PDT. These compounds have strong absorption in 660-670 nm with high molar extinction coefficient, and fluorescence emission in 660-675 nm upon excitation with 410-415 nm light. They all have much higher ROS yields than pyropheophorbide-a, and compound 10 was even higher than [3-(1-hexyloxyethyl)]-pyrophoeophorbide a (HPPH). Distinctive phototoxicity was observed in vitro and the inhibition effect was in light dose-dependent and drug dose-dependent style. They can effectively inhibit the growth of lung tumor in vivo. Among them, compound 8 and 11 have outstanding photodynamic anti-tumor effects without obvious skin photo-toxicity, so they can act as new drug candidates for photodynamic therapy.

FGF-2-mediated FGFR1 signaling in human microvascular endothelial cells is activated by vaccarin to promote angiogenesis.

Angiogenesis is a complex physiological process involving the growth of new capillaries. The impaired angiogenesis plays important roles in chronic wounds and ischaemic heart disease. Fibroblast growth factor 2 (FGF-2) exerts pro-angiogenic actions via activation of fibroblast growth factor receptor 1 (FGFR-1). We have identified that vaccarin increased the angiogenic activity of endothelial cells. In this study, we investigated whether FGF-2-mediated FGFR1 signaling pathway participated in vaccarin-mediated neovascularization formation. Human microvascular endothelial cells (HMEC)-1 were incubated with various doses of vaccarin. Our results showed that vaccarin dose-dependently up-regulated FGF-2 levels and phosphorylation of FGFR-1. Neutralization of FGF-2 with anti-FGF-2 antibody also abolished the proliferation, migration and tube formation of HMEC-1 cells induced by vaccarin. Both FGFR-1 inhibitor SU5402 and FGFR-1 siRNA blocked vaccarin-induced cell cycle progression and angiogenesis. The mouse Matrigel model study further unveiled that vaccarin stimulated the neovascularization and microvessel density in vivo, which was prevented by FGFR-1 inhibitor SU5402. Taken together, our results demonstrated for the first time that vaccarin was a novel inducer for FGF-2 expression, followed by phosphorylation of FGFR-1 and subsequent angiogenic behaviors in endothelial cells. Vaccarin may be a promising candidate of angiogenesis activator for neurovascular repair or therapy.

Endothelial dysfunction and cardiometabolic diseases: Role of long non-coding RNAs.

The vascular endothelium is recognized as a barrier between blood and blood vessel wall. The abnormality of vascular endothelium is critical for atherosclerosis, hypertension and diabetes. Oxidative stress, inflammation, obesity, hyperlipidemia and insulin resistance are major contributors to endothelial dysfunction in cardiovascular disorders. Therapeutic strategies against endothelial dysfunction are developed to prevent and treat vascular lesions. In recent years, long non-coding RNAs (lncRNAs) are emerged as novel modulators in the proliferation and differentiation of various cell types. LncRNAs have attracted considerable attention due to their multiple biological roles in the prognostic prediction, diagnosis and treatment of cancers. LncRNAs are also involved in pathogenesis of cardiovascular diseases. However, the correlations between lncRNAs and endothelial dysfunction are still largely obscure. In this review, we will highlight recent updates associated to the importance of lncRNAs in the pathogenesis of endothelial dysfunction in cardiovascular disorders, and the basic molecular mechanisms of lncRNAs in regulation of endothelial function are also discussed. LncRNAs may become promising therapeutic targets in endothelial dysfunction-related diseases.