Involvement of CaM kinase II in impairments of endothelial function and eNOS activity in aortas of type 2 diabetic Goto‐Kakizaki rats

Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1±0.6 compared with −0.3±0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with −1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P≤0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=−0.61, P=0.02) and apoB-100 (r=−0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and apoB-100 concentrations.

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Abstract 557: Type 2 Diabetes is Associated With Impaired High-Density Lipoprotein Endothelial Protective Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.557 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Tomas Vaisar ◽

Erica Couzens ◽

Arnold Hwang ◽

Andrew N Hoofnagle ◽

Carolyn E Barlow ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Cells ◽

Endothelial Function ◽

Lipid Profile ◽

High Density ◽

High Density Lipoproteins ◽

Protective Function ◽

Enos Activity ◽

Sphingosine 1 Phosphate

Aim: One of the hallmarks of diabetes is impaired endothelial function. High density lipoproteins (HDL) can exert protective effects on endothelium stimulating NO production and protecting from inflammation. Previous study suggested that HDL in obese people with diabetes and metabolic syndrome and markedly low HDL-C lost endothelial protective function. We aimed to test whether type 2 diabetes impairs HDL endothelium protective functions in people with otherwise normal lipid profile. Methods: In a case-control study (n=40 per group) nested in the Cooper Center Longitudinal Study, we isolated HDL and measured its ability to stimulate activity of endothelial nitric oxide synthase (eNOS; phosphorylation of Ser1177) in endothelial cells and the ability of HDL to suppress inflammatory response of endothelial cells (NFkB activation). Additionally, we also measured by LCMS levels of sphingosine-1-phosphate (S1P) and plasma P-selectin by ELISA. Results: The HDL in people with type 2 diabetes lost almost 40% of its ability to stimulate eNOS activity (P<0.001) and 20% of its ability to suppress inflammation in endothelial cells ( P <0.001) compared to non-diabetic controls despite similar BMI and lipid profile (HDL-C, LDL-C, TC, TG).The ability of HDL to stimulate eNOS activity was negatively associated with plasma levels of P-selectin, an established marker of endothelial dysfunction (r=–0.32, P <0.001). Furthermore, sphingosine-1-phosphate (S1P) levels were decreased in plasma of people with diabetes ( P =0.017) and correlated strongly with HDL-mediated eNOS activation. Conclusions: Collectively, our data suggest that HDL in individuals with type 2 diabetes loses its ability to maintain proper endothelial function independent of HDL-C, perhaps due to loss of S1P, and may contribute to development of diabetic complications.

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Abstract 14372: Identification of the Genes That Are Involved in Severe Pulmonary Hypertension in Type 2 Diabetic Mice

Circulation ◽

10.1161/circ.142.suppl_3.14372 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Qiuyu Zheng ◽

Atsumi Tsuji-Hosokawa ◽

Jody T Cabrera ◽

Jian Wang ◽

Ayako Makino

Keyword(s):

Pulmonary Hypertension ◽

Endothelial Function ◽

Protein Level ◽

Chronic Hypoxia ◽

Systolic Pressure ◽

Vascular Complications ◽

Hypoxic Exposure ◽

Diabetic Mice ◽

Type 2 Diabetic

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance. Increasing evidence shows that diabetes increases the risks of PH, and diabetic priming leads to severe PH. However, the molecular mechanism by which preconditioning of diabetes results in severe PH is still unknown. It has been shown that endothelium serves as a key regulator of vascular tone, and endothelial cell dysfunction is implicated in the development of PH and diabetes-related vascular complications. Therefore, we identified the genes that contribute to the development of severe PH in diabetic mice with a focus on endothelial function. We first determined the effect of chronic hypoxia (10% O 2 , 4 weeks) on hemodynamics in type 2 diabetic (T2D) mice. We used inducible T2D mice (generated by high-fat diet and a low-dose streptozotocin injection) and spontaneous T2D mice (TALLYHO/Jng). Diabetic mice exhibited a slight increase in right ventricular systolic pressure (RVSP), and chronic hypoxia led to a further rise in RVSP in both inducible and spontaneous T2D mice. We isolated pulmonary endothelial cells (MPEC) from normoxia-exposed control mice (CN), hypoxia-exposed control mice (CH), normoxia-exposed diabetic mice (DN), and hypoxia-exposed diabetic mice (DH) to examine the levels of 92 genes using real-time PCR. Nighty two genes were selected based on their functions, which are significantly related to endothelial function. We found that 27 genes were significantly changed among 4 groups. We then examined the protein levels of genes that were related to apoptosis and glycolysis. Western Blot data indicated that the protein level of GAPDH was significantly increased in CH and DH compared to CN and DN. In addition, hypoxic exposure in diabetic mice (DH) significantly increased HK2 protein level compare to hypoxia-exposed control mice (CH). These data suggest that precondition of diabetes increases susceptibility to developing PH due partly to altering gene expression of HK2 and Gapdh in MPECs. Since HK2 and GAPDH are a crucial regulator of glycolysis, alteration of glycolysis is expected in hypoxia-exposed diabetic mice. Our study revealed the key molecules which could be used for treating severe PH in diabetes.

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