Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction

Abstract

*These authors contributed equally to this work. †These authors contributed equally to this work and are co-senior authors. BACKGROUND AND PURPOSEHeart failure with preserved ejection fraction (HFpEF) is a systemic syndrome driven by co-morbidities, and its pathophysiology is poorly understood. Several studies suggesting that dipeptidyl peptidase 4 (DPP4) might be involved in the pathophysiology of heart failure have prompted experimental and clinical investigations of DPP4 inhibitors in the cardiovascular system. Here we have investigated whether the DPP4 inhibitor sitagliptin affected the progression of HFpEF independently of its effects on glycaemia. EXPERIMENTAL APPROACHSeven-week-old Dahl salt-sensitive rats were fed a high-salt diet for 5 weeks to induce hypertension. Then the rats continued with the high-salt diet and were treated with either sitagliptin (10 mg·kg À1 ) or vehicle for the following 8 weeks. Blood pressure and cardiac function were measured in vivo. Histochemical and molecular biology analyses of myocardium were used to assay cytokines, fibrotic markers, DPP4 and glucagon-like peptide-1 (GLP-1)/GLP-1 receptor. KEY RESULTSTreatment with sitagliptin attenuated diastolic dysfunction, reduced mortality and reduced cardiac DPP4 activity, along with increased circulating GLP-1 and myocardial expression of GLP-1 receptors. Myocardial levels of pro-inflammatory cytokines (TNF-α, IL-6 and CCL2) were reduced. Sitagliptin treatment decreased the levels of endothelial NOS monomer, responsible for generation of ROS, while the amount of NO-producing dimeric form increased. Markers of oxidative and nitrosative stress were decreased. Moreover, increased collagen deposition and activation of pro-fibrotic signalling, inducing elevated myocardial stiffness, were attenuated by sitagliptin treatment. CONCLUSIONS AND IMPLICATIONSSitagliptin positively modulated active relaxation and passive diastolic compliance by decreasing inflammation-related endothelial dysfunction and fibrosis, associated with HFpEF. LINKED ARTICLES IntroductionHeart failure (HF) with preserved ejection fraction (EF) (HFpEF) is a clinical syndrome that affects about half of all patients with HF. The rising prevalence and significant mortality rate, ranging from 10 to 30% per year, carry a remarkable economic and social burden (Chan and Lam, 2013;Ambrosy et al., 2014). In addition to an overt HFpEF, the growing interest in diastolic performance arises from the observation that, also in non-HF subjects, diastolic abnormalities are associated with increased mortality (Schwarzl et al., 2016). Diastolic dysfunction in HFpEF is characterized by slower left ventricle (LV) relaxation, elevated stiffness and increased filling pressure. The pathophysiology of HFpEF is incompletely understood. While the vast majority of HFpEF patients do not have a recognized primary cardiac pathology, they are older, more often female and have high prevalence of comorbidities, such as hypertension, obesity, diabetes, chronic obstructive pulmonary disease, anaemia an...

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Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…Sitagliptin, an oral antihyperglycemic agent of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor class reduced cardiac fibrosis in an experimental model of T2DM . Sitagliptin also reduced inflammation, fibrosis and preserves diastolic function in a rat model of HFpEF . The mechanism has been proposed to be operative through operating through insulin‐dependent mechanisms specifically GLP‐1 …”

“…134 Sitagliptin also reduced inflammation, fibrosis and preserves diastolic function in a rat model of HFpEF. 135 The mechanism has been proposed to be operative through operating through insulin-dependent mechanisms specifically GLP-…”

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