Dipeptidyl peptidase 4 inhibition rescues PKA-eNOS signaling and suppresses aortic hypercontractility in male rats with heart failure

Author(s)

Fontes, Milene T. ; Arruda-Junior, Daniel F. ; dos Santos, Danubia Silva ; Ribeiro-Silva, Joao Carlos ; Anto, Edinei L. ; Tucci, Paulo F. J. ; Rossoni, Luciana V. ; Girardi, Adriana C. C.

• Document type: Journal article
• Source: Life Sciences; v. 323, p. 10-pg., 2023-04-21.

Abstract

Aims: Vascular dysfunction and elevated circulating dipeptidyl peptidase 4 (DPP4) activity are both reported to be involved in the progression of heart failure (HF). While the cardiac benefits of DPP4 inhibitors (DPP4i) have been extensively studied, little is known about the effects of DPP4i on vascular dysfunction in nondiabetic HF. This study tested the hypothesis that vildagliptin (DPP4i) mitigates aortic hyperreactivity in male HF rats. Materials and methods: Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation to HF induction or sham operation (SO). Six weeks after surgery, radiofrequency-ablated rats who developed HF were treated with vildagliptin (120 mg center dot kg(-1)center dot day(-1)) or vehicle for 4 weeks. Thoracic aorta reactivity, dihydroethidium fluorescence, immunoblotting experiments, and enzyme-linked immunosorbent assays were performed. Key findings: DPP4i ameliorated the hypercontractility of HF aortas to the alpha-adrenoceptor agonist phenylephrine towards SO levels. In HF, the reduced endothelium and nitric oxide (NO) anticontractile effect on phenylephrine response was restored by DPP4i. At the molecular level, this vasoprotective effect of DPP4i was accompanied by (i) reduced oxidative stress and NADPH oxidase 2 (Nox2) expression, (ii) enhanced total endothelial nitric oxide synthase (eNOS) expression and phosphorylation at Ser1177, and (iii) increased PKA activation, which acts upstream of eNOS. Additionally, DPP4i restored the higher serum angiotensin II concentration towards SO. Significance: Our data demonstrate that DPP4i ameliorates aortic hypercontractility, most likely by enhancing NO bioavailability, showing that the DPP4i-induced cardioprotection in male HF may arise from effects not only in the heart but also in conductance arteries. (AU)

• FAPESP's process: 14/17135-9 - Posttranscriptional and posttranslational regulation of the enzyme dypeptidil peptidase IV in heart failure
• Grantee: Daniel Francisco de Arruda Junior
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/08907-3 - The influence of perivascular adipose tissue on vascular reactivity of myocardial infarction rats submitted to combined training
• Grantee: Luciana Venturini Rossoni
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/20303-0 - Evaluation of the influence of perivascular adipose tissue (PVAT) on vascular reactivity of the aorta of infarcted rats submitted to aerobic and resistance training
• Grantee: Milene Tavares Fontes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/05431-3 - Mechanisms responsible for cardioprotective effects of SGLT2 inhibitors: molecular, functional and translational approach
• Grantee: Danúbia Silva dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/22140-7 - Molecular bases of renal tubular function and dysfunction
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/10619-8 - Dipeptidyl peptidase IV as a potential target for the therapy of heart failure
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Regular Research Grants