Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, SP, Brazil.
Life Sci. 2023 Jun 15;323:121648. doi: 10.1016/j.lfs.2023.121648. Epub 2023 Mar 29.
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.
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⸱kg⸱day) or vehicle for 4 weeks. Thoracic aorta reactivity, dihydroethidium fluorescence, immunoblotting experiments, and enzyme-linked immunosorbent assays were performed.
DPP4i ameliorated the hypercontractility of HF aortas to the α-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.
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.
血管功能障碍和循环中二肽基肽酶 4（DPP4）活性升高都与心力衰竭（HF）的进展有关。虽然 DPP4 抑制剂（DPP4i）的心脏益处已被广泛研究，但对于 DPP4i 对非糖尿病 HF 患者血管功能障碍的影响知之甚少。本研究旨在检验假设，即维格列汀（DPP4i）可减轻雄性 HF 大鼠的主动脉高反应性。
雄性 Wistar 大鼠接受左心室（LV）射频消融以诱导 HF 或假手术（SO）。手术后 6 周，HF 发展的射频消融大鼠用维格列汀（120mg·kg·天）或载体治疗 4 周。进行了胸主动脉反应性、二氢乙啶荧光、免疫印迹实验和酶联免疫吸附测定。
DPP4i 改善了 HF 主动脉对α-肾上腺素能激动剂去氧肾上腺素的超收缩性，使其恢复到 SO 水平。在 HF 中，DPP4i 恢复了对去氧肾上腺素反应的内皮和一氧化氮（NO）抗收缩作用的降低。在分子水平上，这种 DPP4i 的血管保护作用伴随着（i）氧化应激和 NADPH 氧化酶 2（Nox2）表达减少，（ii）总内皮型一氧化氮合酶（eNOS）表达和 Ser1177 磷酸化增强，以及（iii）PKA 激活增加，这在上游作用于 eNOS。此外，DPP4i 将更高的血清血管紧张素 II 浓度恢复到 SO 水平。
我们的数据表明，DPP4i 可改善主动脉的高收缩性，这可能是通过增强 NO 的生物利用度来实现的，表明 DPP4i 在雄性 HF 中的心脏保护作用可能不仅来自心脏，还来自传导动脉。
