Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

Mammi, Caterina; Pastore, Donatella; Lombardo, Marco; Ferrelli, Francesca; Caprio, Massimiliano; Consoli, Claudia; Tesauro, Manfredi; Gatta, Lucia; Fini, Massimo; Federici, Massimo; Sbraccia, Paolo; Donadel, Giulia; Bellia, Alfonso; Rosano, Giuseppe M.C.; Fabbri, Andrea; Lauro, Davide

doi:10.1371/journal.pone.0014542

Cited by 51 publications

(42 citation statements)

References 37 publications

(41 reference statements)

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“…22 Lastly, sildenafil has been shown to cause vessel dilation by inhibiting cGMP-specific phosphodiesterase type 5, which degrades cGMP and hence results in elevated level of cGMP that leads to smooth muscle relaxation, thus its effects on vessel relaxation were not expected to be endothelial specific. 23 However, in a recent study, sildenafil was also reported to increase expression of nitric oxide synthase in human endothelial cells 24 motivating the study of sildenafil here.…”

Section: Drug Induced Nitric Oxide Secretion and Monocyte Adhesionmentioning

confidence: 89%

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

et al. 2013

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Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vasoactive drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-a. V C 2013 AIP Publishing LLC. [http://dx

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Section: Drug Induced Nitric Oxide Secretion and Monocyte Adhesionmentioning

confidence: 89%

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

et al. 2013

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“…Although the precise mechanism of HbA 1c reduction upon inhibition of PDE5 is unclear, preclinical and clinical studies suggest that PDE5 inhibition may favorably impact glucose metabolism in T2DM by mediating enhanced glucose uptake in skeletal muscle 22,23 improving b-cell function and decreasing insulin resistance. [24][25][26] Such mechanisms may eventually contribute to the improvement in microvascular disease and subsequent reduction of albuminuria in studies of longer treatment duration with PF-0048971. In addition, a large set of preclinical studies conducted in animal models of diabetic and nondiabetic kidney disease have demonstrated the beneficial effect of PDE5 inhibition on pathophysiological pathways implicated in albuminuria, glomerulosclerosis, and tubulointerstitial injury.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

Scheele

Diamond

Gale

et al. 2016

JASN

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Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m 2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio .300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN. The global prevalence of diabetes mellitus (DM) is increasing, with more than 400 million people projected to be affected by 2030.

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“…Furthermore, hyperinsulinemia during IR can cause vascular disease by promoting synthesis of lipophilic analogs and stimulating the proliferation of smooth muscle cells of the vessel endangium (19). Indeed, high levels of insulin can stimulate synthesis and release of endothelin (ET-1) from endothelial cells, and ET-1 can combine with the endothelin receptor in smooth muscle cells of the endangium to produce strong vasoconstriction (20).…”

Section: Discussionmentioning

confidence: 99%

Association of APOE polymorphisms and insulin resistance with TCM syndromes in type 2 diabetes patients with macroangiopathy

Xie

Wang

et al. 2011

Mol Med Report

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Abstract.To investigate the association between apolipoprotein E (APOE) polymorphisms and insulin resistance and Traditional Chinese Medicine (TCM) syndromes in type 2 diabetes mellitus (T2DM) with macroangiopathy, 60 patients with T2DM macroangiopathy were enrolled and divided into three groups: dryness-heat due to deficiency of yin, Qi-Yin deficiency, and Yin-Yang deficiency, according to the TCM syndromes, with a control group of 20 healthy individuals. APOE genotype analysis was performed with polymerase chain reaction amplification and restriction fragment length polymorphism, and the results showed that the proportion of the ε4/4 and ε3/4 genotypes and frequencies of the ε4 and ε3 alleles were higher in the Qi-Yin deficiency group (P<0.05). Among the T2DM macroangiopathy patients, the E4 group had the largest number of cases, as well as a significantly longer disease course compared to the E2 group (P<0.05). The insulin resistance index (IRI), insulin action index and body mass index (BMI) of patients in the Yin-Yang deficiency group were significantly different from those of patients with dryness-heat due to deficiency of yin and Qi-Yin deficiency. Furthermore, correlation analysis of the BMI and IRI of patients in the Yin-Yang deficiency group revealed a correlation coefficient r= 0.696 (P<0.01) and a typical correlation between them. In conclusion, the Qi-Yin deficiency in T2DM patients with macroangiopathy is associated with the APOE E4 and E3 genotypes. Thus, the APOE gene polymorphism can, to some degree, reflect the TCM syndrome types of T2DM patients with macroangiopathy. Insulin resistance plays an important role in the occurrence of T2DM macroangiopathy and is closely associated with the Yin-Yang deficiency according to the TCM differentiating types.

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Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

Cited by 51 publications

References 37 publications

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

Association of APOE polymorphisms and insulin resistance with TCM syndromes in type 2 diabetes patients with macroangiopathy

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