Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats

Abstract

BackgroundWe investigated whether attenuating dipeptidyl peptidase-IV (DPP4) enzyme activity protected rat heart from ischemia-reperfusion (IR) injury (40-min left anterior descending coronary artery ligation followed by 72 h reperfusion).Methods and resultsAdult male Fischer 344 rats (n = 24) were equally divided into sham-control (WT-SC), WT-IR, and WT-IR-Sita (oral sitagliptin 400 mg/kg/day for 3 days) groups, whereas adult male DPP4-deficiency (DPP4D) rats (n = 16) were equally divided into DPP4D-SC and DPP4D-IR groups. Animals were sacrificed at 72 h after reperfusion with collection of heart specimens. Infarct area (H&E), collagen deposition (Sirius-red stain), fibrotic area (Masson's trichrome), and fluorescent-ROS intensity (H2DCFDA-labeling myocardium) of left ventricle were significantly higher in WT-IR than those in other groups, significantly higher in WT-IR-Sita and DPP4D-IR groups than in WT-SC and DPP4D-SC groups (all p < 0.001), but there was no difference between the latter two groups. Protein expressions of oxidative stress (oxidized protein), reactive oxygen species (NOX-1, NOX-2), inflammation (TNF-α, NF-κB, MMP-9, VCAM-1), apoptosis (mitochondrial Bax, cleaved caspase-3 and PARP), myocardial damage markers (cytosolic cytochrome-C, γ-H2AX), and number of inflammatory cells (CD14+, CD68+, CD40+ cells) showed a pattern identical to that of histological changes among all groups (all p < 0.005), whereas markers of anti-apoptosis (Bcl-2) and mitochondrial integrity (mitochondrial cytochrome-C) as well as left ventricular ejection fraction showed an opposite pattern (all p < 0.001). Protein expressions of anti-oxidants (HO-1, NQO-1), angiogenesis factors (SDF-1α, CXCR4), and glycogen-like-peptide-1-receptor were significantly higher inWT-IR-Sita and DPP4D-IR than those in other groups (all p < 0.001).ConclusionAbrogation of DPP4 activity protects against myocardial IR injury and preserved heart function.

Dipeptidyl Peptidase-IV Inhibition for the Treatment of Cardiovascular Disease ― Recent Insights Focusing on Angiogenesis and Neovascularization ―

“…42 Theirs was the first study using a DPP-IV deletion rat model to validate the role of DPP-IV in ischemia-induced angiogenesis. Based on these findings and those of their previous studies, 39, 43 Sun et al pointed out the lack of SDF-1a concentration gradients between the BM and circulation in DPP-IV −/− rats after ischemic surgery, and they suggested this may be attributable to compensatory increases in other blood SDF-1 degradation DPP-IV inhibition ameliorated circulating pro-angiogenic cell numbers and angiogenesis via an SDF-dependent signal in ischemic PAD patients with T2DM. 5, 24 Collectively, these findings indicated that regulation of SDF-1 activity by inhibiting DPP-IV activity could present a common mechanism in the protection of cardiovascular tissues against ischemic stress.…”

“…5, 24 The ability of pharmacological DPP-IV inhibition to increase blood SDF-1 levels is likely to contribute to the stimulation of revascularization under ischemic experimental conditions in mice. 25, 43 In addition, in rat and mouse acute myocardial ischemic injury models, experimental observations revealed that the prevention of SDF-1 degradation by DPP-IV inhibition led to an enhancement of C-X-C family (SDF-1) receptor (CXCR + ) circulating progenitor cells. 45,46…”

Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy

“…IF staining was performed using the respective primary antibodies for examination of CD31 1 (1:100, Abcam), g-H2AX 1 (1:500, Abcam), Ku-70 (1:100, Abcam), CD90 1 (1:100, abcam), XRCC1 1 (1:200, Abcam), and 53BP1 1 (1:100, Abcam; 1:300, Novus Littleton, CO) cells and actinin-phalloidin (1:500, LuBio Science, Switzerland; 1:500, Life Technologies Carlsbad, CA) in LV myocardium based on recent studies (Rajagopalan et al, 1988;Kim et al, 1989;Arola et al, 2000;Wu et al, 2000). Moreover, immunohistochemical staining was performed for examinations of Sca-1 1 (1:300, BioLegend San Diego, CA) and C-kit 1 (1:300, Santa Cruz) cells using the respective primary antibodies as described previously (Sung et al, 2009;Leu et al, 2011;Chen et al, 2014a,b;Chua et al, 2014). Irrelevant antibodies were used as controls in the current study.…”

“…The procedure and protocol have been described in previous reports (Leu et al, 2011;Chua et al, 2014). Masson's trichrome staining was used to identify fibrosis of the LV myocardium.…”

Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice

“…Histological quantification of myocardial fibrosis and collagen deposition in RV The procedure and protocol were described in detail in our previous report [25] . In detail, Masson's trichrome staining was used for identifying the fibrosis of RV myocardium.…”