PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial

Fiore, Daniela; Gianfrilli, Daniele; Giannetta, Elisa; Galea, Nicola; Panio, Giuseppe; Dato, Carla Di; Pofi, Riccardo; Pozza, Carlotta; Sbardella, Emilia; Carbone, Iacopo; Naro, Fabio; Lenzi, Andrea; Venneri, Mary Anna; Isidori, Andrea M.

doi:10.1210/jc.2015-4252

Cited by 50 publications

(46 citation statements)

References 41 publications

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“…In vivo administration of antagomir of miR-22 to spontaneously hypertensive rat reduced blood pressure and revealed a new avenue for treatment of hypertension50. We recently demonstrated that sildenafil determined a downregulation of circulating miR-22 in diabetic patients and in adipose tissue of db/db mice31. In the present study, we confirmed the downregulation of miR-22 by sildenafil in diabetic kidney and upregulation of its target BMP7, associated with tissue protection.…”

Section: Discussionsupporting

confidence: 83%

“…It was previously demonstrated that BMP7 is regulated by miR-2230. In light of the observed downregulation of miR-22 in adipose tissue after sildenafil treatment31, we decided to verify whether miR-22 underwent a similar pattern of downregulation in kidney. To this end, we examined miR-22 expression by qPCR, finding that it was downregulated by sildenafil ~3 fold ( P < 0.001), (Fig.…”

Section: Resultsmentioning

confidence: 97%

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Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

Pofi

Fiore

Gaetano

et al. 2017

Sci Rep

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Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5is) exert protective effects in DN improving perivascular inflammation. Using a mouse model of diabetic kidney injury we investigated the protective proprieties of PDE5is on renal hemodynamics and the molecular mechanisms involved. PDE5i treatment prevented the development of DN-related hypertension (P < 0.001), the increase of urine albumin creatinine ratio (P < 0.01), the fall in glomerular filtration rate (P < 0.001), and improved renal resistive index (P < 0.001) and kidney microcirculation. Moreover PDE5i attenuated the rise of nephropathy biomarkers, soluble urokinase-type plasminogen activator receptor, suPAR and neutrophil gelatinase-associated lipocalin, NGAL. In treated animals, blood vessel perfusion was improved and vascular leakage reduced, suggesting preserved renal endothelium integrity, as confirmed by higher capillary density, number of CD31+ cells and pericyte coverage. Analysis of the mechanisms involved revealed the induction of bone morphogenetic protein-7 (BMP7) expression, a critical regulator of angiogenesis and kidney homeostasis, through a PDE5i-dependent downregulation of miR-22. In conclusion PDE5i slows the progression of DN in mice, improving hemodynamic parameters and vessel integrity. Regulation of miR-22/BMP7, an unknown mechanism of PDE5is in nephrovascular protection, might represent a novel therapeutic option for treatment of diabetic complications.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 97%

Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

Pofi

Fiore

Gaetano

et al. 2017

Sci Rep

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“…In this study, we confirmed in the SAT depot the results of sildenafil treatment found in VAT on macrophages and ECs . Additionally, we found that PDE5 activity is required for CCL2 and IFN-γ expressions in AT, and sildenafil may be able to suppress chronic inflammation in obesity by inhibiting the expres- In VAT of obese diabetic mice, we observed that PDE5i led to a significant increase in APs, which indicated a propensity to AT hyperplasia rather than hypertrophy (Fiore, Gianfrilli, et al, 2016).…”

Section: Discussionmentioning

confidence: 72%

Chronic phosphodiesterase type 5 inhibition has beneficial effects on subcutaneous adipose tissue plasticity in type 2 diabetic mice

Fiore

Gianfrilli

Cardarelli

et al. 2018

Journal Cellular Physiology

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Different adipose tissue (AT) depots are associated with multiple metabolic risks. Phosphodiesterase type 5 (PDE5) is involved in adipocyte physiology and PDE5 inhibition may affect adipogenesis and ameliorate white AT quality. The aim of this study is to investigate the distribution of AT and the composition of the stroma-vascular fraction (SVF) of subcutaneous AT (SAT) in type 2 diabetic mice after prolonged treatment with a PDE5 inhibitor, Sildenafil. 18 db/db mice were treated with Sildenafil or vehicle for 12 weeks. AT distribution was monitored and SAT was processed for isolation of SVF by flow cytometry. Sildenafil induced an overall reduction in AT, mainly in visceral AT (VAT), compared with SAT. In Sildenafil-treated mice, the mean change in body weight from baseline positively correlated with VAT, but not with SAT. Characterization of SVF of SAT showed an increase in the frequency of M2 macrophages and endothelial cells in treated mice. Sildenafil improved the maintenance of SAT homeostasis and distribution.

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“…Finally, recent data showed that PDE5 inhibitor treatment in humans reduces EF and upregulates SIRT1 in both serum and subcutaneous fat, opening novel therapeutic strategies for EF remodeling and regulation of SIRT1 to promote healthier fat deposits [36].…”

Section: Discussionmentioning

confidence: 99%

Circulating SIRT1 inversely correlates with epicardial fat thickness in patients with obesity

Mariani

Costantini

Lubrano

et al. 2016

Nutrition, Metabolism and Cardiovascular Diseases

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PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial

Abstract: Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.

Cited by 50 publications

References 41 publications

Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

Chronic phosphodiesterase type 5 inhibition has beneficial effects on subcutaneous adipose tissue plasticity in type 2 diabetic mice

Circulating SIRT1 inversely correlates with epicardial fat thickness in patients with obesity

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