Activation of the renin-angiotensin-aldosterone system is common in hypertension and obesity and contributes to cardiac diastolic dysfunction, a condition for which no treatment currently exists. In light of recent reports that antihyperglycemia incretin enhancing dipeptidyl peptidase (DPP)-4 inhibitors exert cardioprotective effects, we examined the hypothesis that DPP-4 inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)-induced cardiac diastolic dysfunction. Male C57BL/6J mice were infused with either Ang II (500 ng/kg/min) or vehicle for 3 weeks receiving either Saxa (10 mg/kg/d) or placebo during the final 2 weeks. Echocardiography revealed Ang II-induced diastolic dysfunction, evidenced by impaired septal wall motion and prolonged isovolumic relaxation, coincident with aortic stiffening. Ang II induced cardiac hypertrophy, coronary periarterial fibrosis, TRAF3-interacting protein 2 (TRAF3IP2)-dependent proinflammatory signaling [p-p65, p-c-Jun, interleukin (IL)-17, IL-18] associated with increased cardiac macrophage, but not T cell, gene expression. Flow cytometry revealed Ang II-induced increases of cardiac CD45+F4/80+CD11b+ and CD45+F4/80+CD11c+ macrophages and CD45+CD4+ lymphocytes. Treatment with Saxa reduced plasma DPP-4 activity and abrogated Ang II-induced cardiac diastolic dysfunction independent of aortic stiffening or blood pressure. Furthermore, Saxa attenuated Ang II-induced periarterial fibrosis and cardiac inflammation, but not hypertrophy or cardiac macrophage infiltration. Analysis of Saxa-induced changes in cardiac leukocytes revealed Saxa-dependent reduction of the Ang II-mediated increase of cardiac CD11c messenger RNA and increased cardiac CD8 gene expression and memory CD45+CD8+CD44+ lymphocytes. In summary, these results demonstrate that DPP-4 inhibition with Saxa prevents Ang II-induced cardiac diastolic dysfunction, fibrosis, and inflammation associated with unique shifts in CD11c-expressing leukocytes and CD8+ lymphocytes.
Pubmed ID: 28977602 RIS Download
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This polyclonal targets Rabbit CIKS/Nuclear Factor Kappa B Activator 1
View all literature mentionsThis polyclonal targets Periostin
View all literature mentionsThis polyclonal targets Phospho-NF-kappaB p65 (Ser536)
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View all literature mentionsThis monoclonal targets Mouse IL-18/IL-1F4 MAb (Clone 93-10C)
View all literature mentionsThis polyclonal targets Mouse IL-17
View all literature mentionsThis polyclonal targets GAPDH
View all literature mentionsThis monoclonal targets CD16/CD32
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View all literature mentionsThis monoclonal targets CD-45
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View all literature mentionsThis monoclonal targets CD11b
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View all literature mentionsThis unknown targets c-Jun, phospho (Ser63) II
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis unknown targets c-Jun, phospho (Ser63) II
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis monoclonal targets CD4
View all literature mentionsThis monoclonal targets F4/80
View all literature mentionsThis polyclonal targets GAPDH
View all literature mentionsThis monoclonal targets CD11b
View all literature mentionsThis monoclonal targets CD44
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View all literature mentionsThis monoclonal targets CD11c
View all literature mentionsThis monoclonal targets CD-45
View all literature mentionsThis unknown targets
View all literature mentionsThis polyclonal targets Mouse IL-17
View all literature mentionsThis monoclonal targets Mouse IL-18/IL-1F4 MAb (Clone 93-10C)
View all literature mentionsThis polyclonal targets Phospho-NF-kappaB p65 (Ser536)
View all literature mentionsThis monoclonal targets CD16/CD32
View all literature mentionsThis polyclonal targets Mouse CXCL10 / IP-10 / CRG-2
View all literature mentionsThis polyclonal targets Rabbit CIKS/Nuclear Factor Kappa B Activator 1
View all literature mentionsThis polyclonal targets Periostin
View all literature mentionsThis unknown targets c-Jun, phospho (Ser63) II
View all literature mentionsThis polyclonal targets Rabbit CIKS/Nuclear Factor Kappa B Activator 1
View all literature mentionsThis polyclonal targets Periostin
View all literature mentionsThis polyclonal targets Phospho-NF-kappaB p65 (Ser536)
View all literature mentionsThis unknown targets
View all literature mentionsThis monoclonal targets Mouse IL-18/IL-1F4 MAb (Clone 93-10C)
View all literature mentionsThis polyclonal targets Mouse IL-17
View all literature mentionsThis polyclonal targets GAPDH
View all literature mentionsThis monoclonal targets CD16/CD32
View all literature mentionsThis monoclonal targets F4/80
View all literature mentionsThis monoclonal targets CD11b
View all literature mentionsThis monoclonal targets CD8a
View all literature mentionsThis monoclonal targets CD4
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis polyclonal targets Mouse CXCL10 / IP-10 / CRG-2
View all literature mentionsThis monoclonal targets CD-45
View all literature mentionsThis monoclonal targets CD44
View all literature mentionsThis monoclonal targets CD11c
View all literature mentions