sildenafil-citrate and Diabetic-Cardiomyopathies

Interleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli.. IL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100 mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 µM), by ELISA.. Baseline IL-8 was higher in DCM vs. healthy subjects (149.14 ± 46.89 vs. 16.17 ± 5.38 pg/ml, p < 0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 ± 5.9 pg/ml, p < 0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95% confidence interval of 0.772 to 1.0, p < 0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression.. Sildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level.

Topics: Case-Control Studies; Cell Proliferation; Cells, Cultured; Diabetic Cardiomyopathies; Female; Follow-Up Studies; Humans; In Vitro Techniques; Inflammation Mediators; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prognosis; Sildenafil Citrate

cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy.. Fifty-nine diabetic men (60.3 ± 7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [σ], -12.6 ± 3.1; increased left ventricular [LV] torsion [θ], 18.4 ± 4.6°; and increased ratio of LV mass to volume, 2.1 ± 0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro-B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion (Δθ: sildenafil, -3.89 ± 3.11° versus placebo, 2.13 ± 2.35°; P<0.001) and strain (Δσ: sildenafil, -3.30 ± 1.86 versus placebo, 1.22 ± 1.84; P<0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5 ± 11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-β were the only markers affected by active treatment (Δmonocyte chemotactic protein-1: -75.30 ± 159.28 pg/mL, P=0.032; Δtransforming growth factor-β: 5.26 ± 9.67 ng/mL, P=0.009). No changes were found in endothelial function, afterload, or metabolism.. The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action.

Topics: Aged; Cardiac Imaging Techniques; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Follow-Up Studies; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Torsion, Mechanical; Treatment Outcome; Ventricular Remodeling

Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc.

Topics: Chemokine CXCL10; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetic Cardiomyopathies; Female; Humans; JNK Mitogen-Activated Protein Kinases; Male; Middle Aged; Muscle, Skeletal; Myocytes, Cardiac; NF-kappa B; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Sildenafil Citrate; STAT1 Transcription Factor

Background In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphodiesterase 5 Inhibitors; Receptors, Adrenergic, beta-2; Sildenafil Citrate

Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Glucose; Male; Mice; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Donors; Rats; RNA, Long Noncoding; Sildenafil Citrate; Triazenes

T helper 1 (Th1) type cytokines and chemokines are bioactive mediators in inflammation underling several diseases and co-morbid conditions, such as cardiovascular and metabolic disorders. Th1 chemokine CXCL10 participates in heart damage initiation/progression; cardioprotection has been recently associated with sildenafil, a type 5 phosphodiesterase inhibitor. We aimed to evaluate the effect of sildenafil on CXCL10 in inflammatory conditions associated with diabetic cardiomyopathy. We analyzed: CXCL10 gene and protein in human cardiac, endothelial, and immune cells challenged by pro-inflammatory stimuli with and without sildenafil; serum CXCL10 in diabetic subjects at cardiomyopathy onset, before and after 3 months of treatment with sildenafil vs. placebo. Sildenafil significantly decreased CXCL10 protein secretion (IC50 = 2.6 × 10(-7)) and gene expression in human cardiomyocytes and significantly decreased circulating CXCL10 in subjects with chemokine basal level ≥ 930 pg/ml, the cut-off value as assessed by ROC analysis. In conclusion, sildenafil could be a pharmacologic tool to control CXCL10-associated inflammation in diabetic cardiomyopathy.

Topics: Cells, Cultured; Chemokine CXCL10; Diabetic Cardiomyopathies; Gene Expression; Humans; Inflammation; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

To study whether calcium-modulating proteins CASQ2, FKBP12.6 and SERCA2a participate in diabetic cardiomyopathy, and whether the beneficial actions of testosterone, sildenafil or fructose diphosphate Sr (FDP-Sr) in the treatment of diabetic cardiomyopathy result from suppressing these molecules.. Fifty male Sprague-Dawley (SD) rats were divided into five groups. Except for the normal group (non-diabetic), the other four groups were injected with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes. Four weeks after STZ injection, the four groups received sildenafil (12 mg·kg(-1)·d(-1), ig, for 4 week), FDP-Sr (200 mg/kg, ig, for 4 week), testosterone propionate (4 mg·kg(-1)·d(-1), sc, for 4 week), or no treatment, respectively.. In the diabetic rats, blood glucose, free fatty acids, triglycerides, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) were significantly increased, while high-density lipoprotein cholesterol (HDL-C) was significantly reduced, as compared to the non-diabetic rats. Cardiac dysfunction and myocardial hypertrophy of the diabetic rats were associated with increased mRNA and protein expression of iNOS, OBRb, and PKCɛ, while expression of CASQ2, SERCA2a, and FKBP12.6 was significantly down-regulated. Sildenafil and FDP-Sr, but not testosterone, significantly attenuated the biomarker abnormalities, without changing the metabolic abnormalities.. CASQ2, FKBP12.6 and SERCA2a were down-regulated in diabetic cardiomyopathy. Sildenafil and FDP-Sr, but not testosterone, attenuated the cardiac dysfunction in diabetic cardiomyopathy, without changing the metabolic abnormalities, which may results from inhibiting oxidative and inflammatory cytokines and improving calcium homeostasis.

Topics: Androgens; Animals; Blood Glucose; Blotting, Western; Calcium-Binding Proteins; Diabetic Cardiomyopathies; Fructose; Homeostasis; Lipid Metabolism; Male; Myocardium; Oxidative Stress; Phosphodiesterase 4 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sildenafil Citrate; Sulfones; Tacrolimus Binding Proteins