OS 05-08 ELMISARTAN IMPROVES CARDIAC FIBROSIS IN DIABETES THROUGH PPARδ/STAT3 PATHWAY—FROM BEDSIDE TO BENCH

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Abstract

Objective:

Despite the threatening risks of diabetes-induced cardiac fibrosis, less is known to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Peroxisome proliferator-activated receptor δ (PPARδ) emerges as a versatile regulator of metabolic and inflammatory homeostasis. Potentially PPARδ may be a therapeutic target for diabetes induced cardiac fibrosis. In the present study, we investigated the effectiveness of Telmisartan, a unique angiotensin receptor blocker (ARB) that increased the expression of PPARδ, in the improvement of left ventricular remodeling in both diabetic human and rats.

Design and Method:

In this longitudinal, prospective study, we enrolled 15 diabetic patients receiving 12 weeks of Telmisartan (20mg/day) and sequentially followed speckle tracking echocardiography. Using streptozotocin we induced type 1 diabetes rat and measure the cardiac fibrosis post the treatment of Telmisartan In addition, by treated with the agonist or antagonist of PPARδ, the fibrosis associated protein expression in cardiomyocytes was evaluated.

Results:

Post treatment, in patients treated with Telmisartan the two dimensional strain improved significantly compared with the baseline value. Also, compared with sham, this diabetic rat heart developed significant fibrosis, which markedly decreased post the treatment of Telmisartan (30 mg/kg/day, orally) for 7 days. Post the incubation with 30mM high glucose, the rat cardiomyocyte showed a significant down-regulation of PPARδ. Interestingly, the increased expression of fibrosis associated proteins, including signal transducer and activator of transcription 3 (STAT3), matrix metallopeptidase 9 (MMP9) and connective tissue growth factor (CTGF), were attenuated by the co-existence of GW0742, a PPARδ agonist. By either knockdown or inhibition of STAT3, the hyperglycemia related high expressions of CTGF and MMP9 were reversed. Independent from the hyperglycemic incubation, the over-expression of STAT3 led to the similar result. Conversely, in the presence of GSK0660, a PPARδ inhibitor, the protective effects of Telmisartan were diminished.

Conclusions:

Telmisartan improved the hyperglycemia induced cardiac fibrosis through PPARδ/STAT3 pathway.

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