UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMPK-Mediated Induction of Mitophagy.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Pub Date : 2024-10-16 DOI:10.1159/000541569
Zhiqiang Zhuang, Yuxi Zhu, Jun Tao, Yandong Liu, Jie Lin, Chunjie Yang, Chule Dong, Xing Qin, Qun Li, Russel J Reiter, Guizhen Wang, Zhaohui Pei, Jun Ren
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Abstract

Background: Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury although its impact on diabetic cardiomyopathy remains elusive.

Method: Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanism involved. Adult mice were made diabetic using streptozotocin (STZ) while receiving UCF101 (7.15 mg/kg, i.p.) for 6 consecutive days.

Result: STZ evidently evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin1, elevated p62), mitophagy (FUNDC1 and Parkin with elevated TOM20), increased left ventricular (LV) end systolic diameter, dampened fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/relengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effect from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMPK (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, mitophagy inhibitor liensinine and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C.

Conclusion: These findings denote that UCF101 rescues diabetes-instigated alterations in cardiac structure and contraction, likely through AMPK-mediated regulation of mitophagy.

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UCF101 可通过 AMPK 介导的丝裂吞噬作用防止糖尿病诱发的心脏重塑和收缩异常。
背景:众所周知,糖尿病会导致心肌结构和功能发生破坏性异常,但目前仍缺乏有效的治疗方案。选择性蛋白酶抑制剂 UCF101(5-[5-(2-硝基苯基)呋喃碘]-1,3-二苯基-2-硫代巴比妥酸)已被证明可防止缺血性心脏损伤,但其对糖尿病心肌病的影响仍难以捉摸:本研究旨在探讨 UCF101 对糖尿病诱发的心脏几何和功能异常的影响及其机制。用链脲佐菌素(STZ)使成年小鼠患糖尿病,同时连续 6 天接受 UCF101(7.15 mg/kg,静注):结果:STZ 明显诱发心脏肥大、间质纤维化、线粒体超微结构损伤、氧化应激、自噬(LC3B、Beclin1、p62 升高)、有丝分裂(FUNDC1 和 Parkin 以及 TOM20 升高)受阻、左心室收缩末期直径增大、射血分数缩短受阻、心肌细胞体积减小、射血分数降低、在舒张期延长和细胞内 Ca2+ 清除的同时,UCF101 还能明显调和这些反应,而 UCF101 本身几乎没有影响。细胞损伤标志物 Omi/HtrA2、TNFα 和应激信号转导(JNK、ERK、p38)的水平明显升高,细胞燃料 AMPK(Thr172)和细胞存活分子 GSK3β 的磷酸化受到影响,SERCA2a 下调,磷脂兰班升高,UCF101 逆转了这些影响(SERCA2a 除外)。AMPK基因敲除、药物抑制、有丝分裂抑制剂莲心宁和parkin基因敲除使UCF101对糖尿病患者心脏的保护作用无效。UCF101逆转了STZ诱导的AMPK降解酶PP2A和PP2C的上调:这些研究结果表明,UCF101可能通过AMPK介导的有丝分裂调节,挽救糖尿病诱发的心脏结构和收缩的改变。
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来源期刊
Pharmacology
Pharmacology 医学-药学
CiteScore
5.60
自引率
0.00%
发文量
52
审稿时长
6-12 weeks
期刊介绍: ''Pharmacology'' is an international forum to present and discuss current perspectives in drug research. The journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes; research communications of novel therapeutic agents are encouraged.
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