title: Telmisartan improves cardiac fibrosis in diabetes through peroxisome proliferator activated receptor δ (PPARδ): from bedside to bench.
abstract: Despite the known risk of diabetes-induced cardiac fibrosis, less is known about whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Peroxisome proliferator-activated receptor δ (PPARδ), a versatile regulator of metabolic homeostasis, may be a potential therapeutic target. Herein we investigated the effectiveness of telmisartan, a unique angiotensin receptor blocker that increases PPARδ expression, in improving left ventricular remodeling in diabetic humans and rats.
  
  
  
  In this longitudinal, prospective study, we enrolled 15 diabetic patients receiving telmisartan (20 mg/day) for 12 weeks. After treatment, strain was measured and compared with the baseline value. Using streptozotocin to induce type 1 diabetes rat model, we measured PPARδ expression and downstream targets.
  
  
  
  After treatment with telmisartan, both longitudinal and circumferential strains improved in diabetic patients. Compared with that of controls, the diabetic rat heart developed significant fibrosis, which markedly decreased after treatment with telmisartan (30 mg/kg/day, orally) for 7 days. After incubation with 30 mM glucose, rat cardiomyocytes showed a significant down-regulation of PPARδ. Interestingly, the increased expression of fibrosis-associated proteins, including signal transducer and activator of transcription 3 (STAT3) was attenuated by the co-incubation of GW0742, a PPARδ agonist. By knockdown or inhibition of STAT3, the hyperglycemia related high expression of fibrosis associated targets was reversed. Independent from the hyperglycemic incubation, STAT3 over-expression led to similar results. Conversely, in the presence of GSK0660, a PPARδ inhibitor, the protective effects of telmisartan were diminished.
  
  
  
  Telmisartan improved the hyperglycemia-induced cardiac fibrosis through the PPARδ/STAT3 pathway. Graphical abstract Summary of the mechanism of telmisartan's effect on the suppression of hyperglycemia-induced cardiac fibrosis through PPARδ instead of the AMPK pathway. PPARδ peroxisome proliferator-activated receptor δ, STAT3 signal transducer and activator of transcription 3, CTGF connective tissue growth factor, MMP9 matrix metallopeptidase 9.
authors: Department of Cardiology, Chi Mei Medical Center, 901, Zhonghua Road, Yongkang District, Tainan, Taiwan, ROC.
authors: Wei-Ting
authors: WT
authors: Chang
authors: Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.
authors: Juei-Tang
authors: JT
authors: Cheng
authors: Department of Cardiology, Chi Mei Medical Center, 901, Zhonghua Road, Yongkang District, Tainan, Taiwan, ROC. cmcvecho@gmail.com.|Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. cmcvecho@gmail.com.
authors: Zhih-Cherng
authors: ZC
authors: Chen
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D001565:Benzoates / Q000009:adverse effects / Q000627:therapeutic use*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D011446:Prospective Studies; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D000077333:Telmisartan; D013997:Time Factors; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D013311:Streptozocin; D000077333:Telmisartan
keywords: Diabetic cardiomyopathy; PPARδ; STAT3; Telmisartan