Abstract
Much evidence indicates that metabolic syndrome is strongly correlated with a decrease in nitric oxide and an increase in oxidative stress leading to cardiovascular alterations. In recent years, gut microbiota has emerged as a new contributor to the metabolic syndrome establishment and associated cardiovascular diseases, but the underlying mechanisms remain unclear. We hypothesized that a positive modulation of cyclic guanosine monophosphate (cGMP) pathway, through phosphodiesterase type 5 (PDE5) inhibition could prevent cardiovascular alterations and gut dysbiosis that may be associated to metabolic syndrome. Spontaneously hypertensive rats (SHR) were randomly divided into 4 groups: control, cafeteria diet (CD) and sildenafil citrate treated groups (5mg/kg per os) were given either a CD or a standard chow diet for 10 weeks. Body weight, arterial blood pressure and glucose tolerance test were monitored. At the 10th week, cardiac inotropy and coronary perfusion pressure were evaluated on isolated heart according to Langendorff method. Cumulative concentration response curves to phenylephrine and acetylcholine were determined on thoracic aorta rings for vascular reactivity evaluation. Faecal samples were collected for the gut microbiota analysis. Compared to the control group, CD-fed rats showed a significant increase in body weight gain, arterial blood pressure and were glucose intolerant. This group showed also a decrease in β-adrenoceptor-induced cardiac inotropy and coronary vasodilation. Gut microbiota analysis revealed a significant reduction in the abundance of Lactobocillus spp in cafeteria diet-fed rats when compared to the control ones. Sildenafil citrate long-term treatment decreased weight gain and arterial blood pressure, improved coronary vasodilation and reduced α1-adrenoceptor-induced vasoconstriction in CD group. However, it did not reverse gut dysbiosis induced by chronic CD feeding. These results suggest that cGMP pathway targeting may be a potential therapeutic strategy for the management of the metabolic syndrome and associated cardiovascular disorders.
Highlights
Metabolic syndrome is a complex systemic disorder characterized by a cluster of inter-related factors including abdominal obesity, abnormal glucose metabolism, hypertension, insulin resistance, endothelial dysfunction and inflammatory reaction [1,2]
Chronic sildenafil citrate treatment resulted in lower weight gain compared with untreated cafeteria diet (CD)- fed rats (Fig 1)
The decrease in sildenafil-induced arterial blood pressure was greater in the CD group than in the control group (Fig 2A and 2B)
Summary
Metabolic syndrome is a complex systemic disorder characterized by a cluster of inter-related factors including abdominal obesity, abnormal glucose metabolism, hypertension, insulin resistance, endothelial dysfunction and inflammatory reaction [1,2]. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 inhibitors have been reported, suggesting that a pharmacotherapy that elevates intracellular levels of cyclic guanosine monophosphate (cGMP) might be a promising approach to treat metabolic disorders [4,5]. Recent studies have proposed the potential role of gut microbiota as a pathogenic factor affecting host metabolic balance and contributing to the development of metabolic syndrome [7,8]. An altered gut microbiota composition has been demonstrated to cause devastating pathophysiological consequences such as obesity, metabolic disorders or type 2 diabetes [13].
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