Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Agonist Improves Coronary Artery Endothelial Function in Diabetic Patients with Coronary Artery Disease

Yu, Jie; Zhang, Z; Li, Z; Feng, Xing; He, Lan; Liu, S; Mao, Jiandong; Wang, G; Wang, X

doi:10.1177/147323001003800110

Cited by 19 publications

(12 citation statements)

References 22 publications

(9 reference statements)

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“…Our previous studies demonstrated a positive association between CFVR and endothelial function in patients either with type 2 diabetes-associated coronary artery disease or with hyperhomocysteinemia (18,27,39). CFVR could be upregulated by some hypoglycemic and lipid-lowing drugs such as the peroxisome proliferator-activated receptor (PPAR)-␥ agonist rosiglitazone and the PPAR␣ agonist fenofibrate (35,40). In this study, we found that after 12 wk of exenatide treatment, endothelial function of the coronary ar- …”

Section: Discussionmentioning

confidence: 49%

Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

Wei¹,

Ma²,

Wang³

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

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Section: Discussionmentioning

confidence: 49%

Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

Wei¹,

Ma²,

Wang³

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…There is accumulating evidence that activation of PPARγ plays an essential role in the regulation of the vascular endothelial function (Polikandriotis et al ., 2005; Duan et al ., 2008; Yu et al ., 2010). The endothelium is an innermost lining of the blood vessel that is anti‐coagulant and anti‐thrombotic in nature, thus it maintains the free flow of blood through vessels.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, maintaining a normal function of the vascular endothelium by maintaining the normal activation of eNOS and generation of NO in the vascular bed is essential for the prevention of the progression of detrimental cardiovascular disorders. Interestingly, recent studies have demonstrated a key role of PPARγ in regulating the function of the vascular endothelium (Ríos‐Vázquez et al ., 2006; Duan et al ., 2008; Kaur et al ., 2010b; Yu et al ., 2010). There is evidence that activation of PPARγ causes eNOS activation and NO generation involving diverse mechanisms (Calnek et al ., 2003; Cho et al ., 2004; Polikandriotis et al ., 2005).…”

Section: Introductionmentioning

confidence: 99%

Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders

Balakumar

Kathuria

2012

British J Pharmacology

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PPARγ activation plays an important role in glucose metabolism by enhancing insulin sensitization. PPARγ is a primary target for thiazolidinedione-structured insulin sensitizers like pioglitazone and rosiglitazone employed for the treatment of type 2 diabetes mellitus. Additionally, PPARγ activation inhibits adhesion cascades and detrimental vascular inflammatory events. Importantly, activation of PPARγ plays a distinctive role in regulating the physiology and expression of endothelial nitric oxide synthase (eNOS) in the endothelium, resulting in enhanced generation of vascular nitric oxide. The PPARγ activation-mediated vascular anti-inflammatory and direct endothelial functional regulatory actions could, therefore, be beneficial in improving the vascular function in patients with atherosclerosis and hypertension with or without diabetes mellitus. Despite the disappointing cardiac side effect profile of rosiglitazone-like PPARγ full agonists, the therapeutic potential of novel pharmacological agents targeting PPARγ submaximally cannot be ruled out. This review discusses the potential regulatory role of PPARγ on eNOS expression and activation in improving the function of vascular endothelium. We argue that partial/submaximal activation of PPARγ could be a major target for vascular endothelial functional improvement. Interestingly, newly synthesized partial agonists of PPARγ such as balaglitazone, MBX-102, MK-0533, PAR-1622, PAM-1616, KR-62776 and SPPARγM5 are devoid of or have a reduced tendency to cause the adverse effects associated with full agonists of PPARγ. We propose that the vascular protective properties of pharmacological agents, which submaximally activate PPARγ, should be investigated. Moreover, the therapeutic opportunities of agents that submaximally activate PPARγ in preventing vascular endothelial dysfunction (VED) and VED-associated cardiovascular disorders are discussed.

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“…Accumulating evidence indicates that the activation of PPARγ plays an essential role in the regulation of vascular endothelial function by enhancing the expression of endothelial nitric oxide synthase (eNOS) in the endothelium (Balakumar and Kathuria, 2012;Duan et al, 2008;Polikandriotis et al, 2005;Yu et al, 2010). Zhang, et al (2013) reported that rosiglitazone treatment in a rat focal cerebral ischemia model preserved the expression of collagen IV and glucose transporter 1 (GLUT1), which contribute to the energy-associated protection of BBB integrity.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone attenuates early brain injury after experimental subarachnoid hemorrhage in rats

Gu¹,

Wang²,

Li³

et al. 2015

Brain Research

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Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Agonist Improves Coronary Artery Endothelial Function in Diabetic Patients with Coronary Artery Disease

Cited by 19 publications

References 22 publications

Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders

Rosiglitazone attenuates early brain injury after experimental subarachnoid hemorrhage in rats

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