Cardio-renal positive effects of dipeptidyl peptidase 4 inhibitor sitagliptin preserve diastolic function in a model of heart failure with preserved ejection fraction

• Published in: Vascular pharmacology 2018-04, Vol.103-105, p.50-50
• Main Authors: Cappetta, D., De Angelis, A., Ciuffreda, L.P., Esposito, G., D’Amario, D., Siracusano, A., Berrino, L., Rossi, F., Urbanek, K.
• Format: Article
• Language: English
• Subjects: Activation; Blood glucose; Blood pressure; Cardiovascular disease; Chronology; Coexistence; Collagen; Diabetes mellitus; Diagnostic systems; Diet; Dipeptidyl-peptidase IV; Ejection fraction; Fibrosis; Heart; Heart diseases; Hypertension; Identification methods; Inflammation; Inhibitors; Interleukin 6; Kidneys; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Myocardium; Nephropathy; Oxidative stress; Pathophysiology; Peptidase; Proteins; Rats; Reactive oxygen species; Reduction; Renal failure; Renal function; Salts; Signal transduction; Stiffness; Studies; Tumor necrosis factor-α
• ISSN: 1537-1891; 1879-3649
• DOI: 10.1016/j.vph.2017.12.010

Objective: Heart failure (HF) with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) often share co-morbidities like hypertension and diabetes. Moreover, renal dysfunction in HFpEF is common and is associated with increased mortality. Co-existence of heart and kidney failure is a clinical challenge, because of diagnostic and therapeutic difficulties, since many HF medications may cause, or are contraindicated in the presence of renal failure. Several studies suggesting that dipeptidyl peptidase 4 (DPP4) might be involved in the pathophysiology of heart failure prompted investigations of DPP4 inhibitors cardiovascular safety and potential benefits in HFpEF. In addition. DPP4 inhibitors have shown to delay CKD progression in experimental diabetic nephropathy. We aimed 1. to determine whether DPP4 inhibitor sitagliptin (SITA) affects the progression of HFpEF and CKD independently from the effects on glycaemia; 2.to identify mechanisms involved in the potential cardio-renal protection. Methods: Seven-week-old Dahl salt-sensitive (Dahl/SS) rats were fed a high salt diet (8% NaCI) for 5 weeks to induce hypertension. Then, rats continued with a high salt diet and were administered with either SITA (l0 mg·kg-1 by oral gavage) or vehicle for the following 8 weeks. Results: Treatment with SITA attenuated diastolic dysfunction ameliorating hemodynamic indices. During 8 weeks of the treatment with SITA, blood pressure remained markedly elevated, with a slight, but significant reduction observed only at 19 weeks of age. Interestingly. SITA determined a reduction in DPP4 activity in the heart and kidney and an increase in CLP-1 levels in plasma. The link between high blood pressure and cardio-renal damage may involve high levels of oxidative stress and a low-grade systemic inflammation. In fact, levels of pro-inflammatory tumor necrosis factor-α, IL-6 and monocyte chemoattractant protein-1 were elevated in Dahl/SS rats but reduced by SITA treatment. SITA decreased the levels of eNOS monomer, responsible for reactive oxygen species generation, and elevated the amount of NO-producing dimeric form. The markers of oxidative and nitrosative stress were decreased. Oxidative stress and proinflammatory status observed in Dahl/SS rats contribute to activation of pro-fibrotic pathways in the myocardium and kidney. Increase of collagen deposition and activation of pro-fibrotic signalling that leads to elevated myocardial stiffness were attenuated by SITA. Moreov