title: Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice.
abstract: Therapeutic management of diabetic myocardial fibrosis remains an unsolved clinical problem. Pin1, a peptidyl-prolyl isomerase, impacts diverse cellular processes and plays a pivotal role in regulating cardiac pathophysiology. Here we investigate the potential mechanism of action of Pin1 and its role in diabetes-induced myocardial fibrosis and dysfunction in mice. Cardiac Pin1, transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA) and extracellular matrix deposits (collagen I and III) are found to be increased in diabetic mice, which are effectively prevented by Pin1 inhibition by juglone. Pin1 inhibition alleviates cardiac fibrosis and dysfunction. In vitro, high glucose increases Pin1 expression with an accompanying increase in phospho-Akt (Ser 473), p-Smad2, p-Smad3, TGF-β1, and α-SMA in cardiac fibroblasts (CFs). These increases are effectively prevented by the inhibition of Pin1 by juglone. Furthermore, Pin1 inhibition inhibits HG-induced CF proliferation and migration. Our results indicate that Pin1 inhibition attenuates cardiac extracellular matrix deposition by regulating the phosphorylation of Akt, TGF-β1/Smads, MMP activities, and α-SMA expression in diabetic mice.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China; Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Ershun
authors.initials: E
authors.lastname: Liang
authors.affiliation: The People's Hospital of JimoCity, Qingdao, Shandong 266200, China.
authors.forename: Xiuhui
authors.initials: X
authors.lastname: Song
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Zhanhui
authors.initials: Z
authors.lastname: Du
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China. Electronic address: yxzhao@sdu.edu.cn.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000517:prevention & control; D005947:Glucose / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D024061:Collagen Type III; D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D051896:Smad Proteins, Receptor-Regulated; D053773:Transforming Growth Factor beta1; D051057:Proto-Oncogene Proteins c-akt; C000606850:Pin1 protein, mouse; D005947:Glucose; C005134:juglone
keywords: Diabetic cardiomyopathy; Fibrosis; Pin1; TGF-β1