The contributions of dipeptidyl peptidase IV to inflammation in heart failure

Abstract

Circulating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-α, IL-1β, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression.

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

“…In our study, sitagliptin treatment reversed TNF‐α and IL‐6 increases in the myocardium. This observation is consistent with previous reports demonstrating an anti‐inflammatory effect of sitagliptin in different experimental models, such as Zucker diabetic fatty rats, ApoE −/− mice, spontaneously hypertensive rats and in a LV radiofrequency ablation model of HF (Ferreira et al, ; Ta et al , ; Matsubara et al, ; Lee et al, ; de Almeida Salles et al, ).…”

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

“…This gliptin exerted vasculoprotective effects in mice and rats . Anti‐inflammatory, antioxidative, antifibrotic, and antiapoptotic effects were evidenced in myocardium of mice, rats, and pigs . It showed protective effects in mice and rat kidneys .…”

“…In myocardial ischemia‐reperfusion rat model pretreatment with sitagliptin administered by intraperitoneal injection at 300 mg/kg daily for 2 weeks decreased lactate dehydrogenase, creatine kinase‐MB and MDA levels, Bax/Bcl‐2 ratio, while increased levels of superoxide dismutase (SOD), glutathione peroxidase (GSHPx), GLP‐1 with the activation of GLP‐1 receptor signaling as suggested underlying mechanism . Administered orally at dose of 200 mg/kg daily for 6 weeks, sitagliptin improved cardiac function, reduced levels of IL‐1β, ‐6, MCP‐1, TNF‐α, iNOS, and macrophage infiltration in rat experimental model of heart failure . In pigs with induced heart failure, sitagliptin administered orally at 30 mg/kg once daily for 4 weeks, suppressed myocardial expression of IL‐6 and MCP‐1 .…”

Cardiovascular effects of sitagliptin – An anti‐diabetes medicine

“…Also, the myocardial ischaemia/reperfusion (I/R)‐induced cardiac dysfunction can also be improved by sitagliptin pre‐treatment, presented as decreased creatine kinase‐MB (CK‐MB) and lactate dehydrogenase (LDH), as well as enhanced left ventricular end systolic pressure and LV d p /d t max . In experimental heart failure models, sitagliptin‐treated rats exerted better cardiac function, and the cardiac remodelling and pulmonary congestion were also improved …”

“…As reported in an experimental model, at the onset and during the progression of heart failure, the vicious cycle of DPP‐4 activity and inflammation was observed. Once the DPP‐4 activity was interfered by sitagliptin, the vicious cycle can be aborted, which exerted protective effects . The anti‐inflammatory agents of sitagliptin aroused by GLP‐1 also participated in its anti‐atherosclerotic and endothelium‐protective effects .…”