Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart Failure

Santos, Leonardo dos; Salles, Thiago A.; Arruda-Junior, Daniel F.; Campos, Luciene Cristina Gastalho; Pereira, Alexandre C.; Barreto, Ana Luiza T.; Antônio, Ednei Luiz; Mansur, Alfredo José; Tucci, Paulo José Ferreira; Krieger, José Eduardo; Girardi, Adriana C. C.

doi:10.1161/circheartfailure.112.000057

Cited by 100 publications

(122 citation statements)

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“…Exendin-4 and DPP4 attenuated cardiac remodeling in rat diabetic cardiomyopathy by reducing cardiac fibrosis (5). It was reported that GLP-1 and the exendin-4 analog AC3174 prevented cardiac remodeling in post-MI rat heart (18), which is supported by a recent clinical investigation showing that circulating dipeptidyl peptidase-4 activity is well correlated with cardiac dysfunction in human heart failure (11). The present study demonstrated that exendin-4 mitigates the hypertrophic response and prevented the deposition of collagen content, which was abrogated by depletion of MKK3 and Akt-1.…”

Section: Discussionmentioning

confidence: 82%

“…Exendin-4 treatment resulted in a decrease in cleaved PARP and active caspase-3; these decreases were abrogated by deletion of MKK3 and Akt-1. LV ablationinduced heart failure in rats treated with the DPP4 inhibitor, sitagliptin, attenuated cardiac remodeling and cardiomyocyte apoptosis (11). Delivery of GLP-1 encapsulating genetically modified mesenchymal stem cells in a post-MI pig improved LV function and reduced epicardial infarct size, which was associated with increased angiogenesis and an altered remodeling response (37).…”

Section: Discussionmentioning

confidence: 99%

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Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

Zhang

Wang

et al. 2016

American Journal of Physiology-Cell Physiology

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-We have demonstrated that glucagon like peptide-1 (GLP-1) protects the heart against ischemic injury. However, the physiological mechanism by which GLP-1 receptor (GLP-1R) initiates cardioprotection remains to be determined. The objective of this study is to elucidate the functional roles of MAPK kinase 3 (MKK3) and Akt-1 in mediating exendin-4-elicited protection in the infarcted hearts. Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Wild-type, MKK3Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ; MKK3 Ϫ/Ϫ mice were divided into one of several groups: 1) sham: animals underwent thoracotomy without ligation; 2) MI: animals underwent MI and received a daily dose of intraperitoneal injection of vehicle (saline); 3) MI ϩ exendin-4: infarcted mice received daily injections of exendin-4, a GLP-1R agonist (0.1 mg/kg, ip). Echocardiographic measurements indicate that exendin-4 treatment resulted in the preservation of ventricular function and increases in the survival rate, but these effects were diminished in MKK3 Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ;MKK3 Ϫ/Ϫ mice. Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis, respectively, but these beneficial effects were lost in genetic elimination of MKK3, Akt-1, or Akt-1 Ϫ/Ϫ ;MKK3 Ϫ/Ϫ mice. GLP-1R stimulation stimulated angiogenic responses, which were also mitigated by deletion of MKK3 and Akt-1. Exendin-4 treatment increased phosphorylation of MKK3, p38, and Akt-1 at Ser129 but decreased levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase; these proteins were diminished in MKK3 Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ; MKK3 Ϫ/Ϫ mice. These results reveal that exendin-4 treatment improves cardiac function, attenuates cardiac remodeling, and promotes angiogenesis in the infarcted myocardium through MKK3 and Akt-1 pathway.glucagon-like peptide-1 receptor; MAPK kinase 3; Akt-1; myocardial infarction; function GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is a naturally occurring incretin that is implicated in the control of appetite and satiety (23). GLP-1 has been studied extensively in type 2 diabetes as a novel insulinotropic peptide whose actions are dependent on the ambient glucose concentration. GLP-1 acts through the GLP-1 receptor (GLP-1R), a 463-amino acid member of the G protein-coupled receptor superfamily (23). GLP-1 is rapidly cleaved by dipeptidyl-peptidase-4 (DPP4), which results in the generation of largely inactive molecular GLP-1 9 -36 amide and GLP-1 9 -37 forms (14). The majority of GLP-1 leaving the intestinal venous circulation has already been cleaved by DPP4 expressed in capillary surrounding gut L cells, which provides an estimated half-life of 1-2 min for intact GLP-1 in vivo (12). The GLP-1 receptor is widely distributed in tissues, including brain, pancreas, intestine, lung, stomach, and kidney. Recently, multiple GLP-1 receptor agonists with longer duration of effect in vivo have been explored, among which is exendin-4, a 39-amino acid peptide that shares 53% sequence ho...

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

Zhang

Wang

et al. 2016

American Journal of Physiology-Cell Physiology

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“…Emerging evidence suggests that DPPIV inhibitors, also known as gliptins, may provide cardiovascular benefits beyond glycemic control (1,3,4,13,23,40). In fact, genetic deletion or pharmacological inhibition of DPPIV improves cardiovascular outcomes after myocardial infarction in both normoglycemic and diabetic mice (42).…”

Section: This Study Shows That Dipeptidyl Peptidase IV (Dppiv) Inhibimentioning

confidence: 99%

“…In fact, genetic deletion or pharmacological inhibition of DPPIV improves cardiovascular outcomes after myocardial infarction in both normoglycemic and diabetic mice (42). In addition, increased DPPIV activity in the plasma significantly correlates with poorer prognosis, including cardiac dysfunction and mortality in patients with heart failure (HF) (13,26,46).…”

Section: This Study Shows That Dipeptidyl Peptidase IV (Dppiv) Inhibimentioning

confidence: 99%

The contributions of dipeptidyl peptidase IV to inflammation in heart failure

Salles

Zogbi

Lima

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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“…DPP‐4 cleaves the N‐terminal portion from intact brain natriuretic peptide (BNP) 1–32 , yielding BNP 3–32 that displays significantly reduced myocardial, vascular, and renal effects versus the full peptide 11, 12, 13. DPP‐4 has also been shown to reduce NO bioavailability 14.…”

Section: Introductionmentioning

confidence: 99%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

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Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart Failure

Cited by 100 publications

References 32 publications

Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

The contributions of dipeptidyl peptidase IV to inflammation in heart failure

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

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