ASSA13-06-6 Prevention of Cardiac Remodelling by Gene Silencing of Toll-Like Receptor-4 in Mice with Diabetic Cardiomyopathy

Abstract

<h3>Objective</h3> Left ventricular (LV) remodelling contributes to the development of cardiac dysfunction and is considered as a key determinant of morbidity, mortality and prognosis in patients who developed diabetic cardiomyopathy (DCM). Stimulation of toll-like receptor 4 (TLR4) can lead to impairment of myocyte contractility and activation of several intracellular mediators such as kinases, which are known as critical regulators of myocardial remodelling. Up-regulation of TLR4 expression has been shown in myocardial tissue of diabetic mice. This work is aimed to investigate whether TLR4 has influences on cardiac function and remodelling in a mouse model of DCM. <h3>Methods</h3> Diabetes was induced in C57/B16 mice by the intraperitoneal injection of streptozotocin. Diabetic mice were treated with TLR4 siRNA or scrambled siRNA as control once a week. After treatment for 6 weeks, echocardiographic parameters and invasive cardiac function detection were performed. LV tissues were collected for the assessment of collagen density and cardiomyocyte hypertrophy. Meanwhile, the expression of myeloid differentiation factor 88 (MyD88) and c-Jun N-terminal kinases (JNK) were also detected by real- time PCR and western blot. <h3>Results</h3> Compared with diabetic mice and scrambled siRNA treated diabetic mice, TLR4 siRNA treated diabetic mice showed improved systolic and diastolic LV functions and decreased LV remodelling as evidenced by reduced collagen density and levels of plasma atrial natriuretic peptide. Interstitial fibrosis and myocardial hypertrophy were also reduced by TLR4 siRNA treatment. These were associated with down- regulations of intracellular TLR4 adapter MyD88 and significantly increased expression of the anti-hypertrophic JNK, suggesting the JNK pathway may be also involved in TLR4 triggered LV remodelling in DCM. <h3>Conclusions</h3> In summary, we present direct evidence that TLR4 plays a critical role in cardiac remodelling in DCM. TLR4 may be a novel therapeutic target in the treatment of DCM.