Okabe Kosuke, Matsushima Shouji, Ikeda Soichiro, Ikeda Masataka, Ishikita Akihito, Tadokoro Tomonori, Enzan Nobuyuki, Yamamoto Taishi, Sada Masashi, Deguchi Hiroko, Shinohara Keisuke, Ide Tomomi, Tsutsui Hiroyuki
From the Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan (K.O., S.I., M.I., A.I., T.T., N.E., T.Y., M.S., H.D., H.T.).
Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan (S.M.).
Hypertension. 2020 Apr;75(4):991-1001. doi: 10.1161/HYPERTENSIONAHA.119.14400. Epub 2020 Mar 11.
Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II-induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II-induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II-induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II-induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II-induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes.
Nox4（烟酰胺腺嘌呤二核苷酸磷酸氧化酶4）是氧化应激的主要来源，与心脏肥大密切相关。据报道，二肽基肽酶（DPP）-4抑制剂可调节脂肪组织中Nox4的表达。然而，其对心脏肥大中Nox4的影响仍不清楚。我们研究了DPP-4抑制剂是否能通过调节Nox4及其下游靶点来改善心脏肥大。将血管紧张素II（Ang II；每天1.44 mg/kg）或生理盐水持续输注到饮用含或不含替格列汀（一种DPP-4抑制剂，每天30 mg/kg）的饮用水的C57BL/6J小鼠体内，持续1周。替格列汀显著抑制血浆DPP-4活性，而对主动脉血压或血糖和胰岛素水平等代谢参数无显著影响。它减轻了Ang II诱导的左心室壁厚度增加以及心脏重量与体重之比的增加。它还显著抑制了Ang II诱导的心脏中Nox4 mRNA、4-羟基-2-壬烯醛以及HDAC4（组蛋白去乙酰化酶4）磷酸化的增加，HDAC4是Nox4的下游靶点，也是心脏肥大的关键抑制因子。胰高血糖素样肽-1（GLP-1）受体拮抗剂艾塞那肽-3（每分钟150 pmol/kg）消除了替格列汀对Nox4、4-羟基-2-壬烯醛、HDAC4磷酸化以及心脏肥大的这些抑制作用。在培养的新生心肌细胞中，GLP-1受体激动剂艾塞那肽-4（100 nmol/L，24小时）改善了Ang II诱导的心肌细胞肥大，并降低了Nox4、4-羟基-2-壬烯醛以及HDAC4的磷酸化。此外，艾塞那肽-4可防止Ang II诱导的心肌细胞核内HDAC4减少。总之，DPP-4抑制剂刺激GLP-1受体可通过抑制心肌细胞中的Nox4-HDAC4轴来减轻Ang II诱导的心脏肥大。
