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April 13, 2020Diabetes TherapyOpen Access

Systemic Delivery of siRNA Specific for Silencing TLR4 Gene Expression Reduces Diabetic Cardiomyopathy in a Mouse Model of Streptozotocin-Induced Type 1 Diabetes

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Key result

Systemic delivery of TLR4 siRNA significantly preserved left ventricular ejection fraction (57.95% vs. 45.34%) and reduced hypertrophy, fibrosis, and inflammation in a mouse model of diabetic cardiomyopathy.

Why the study?

TLR signaling triggers diabetic cardiomyopathy through mechanisms including TLR4 upregulation, prompting this study to delineate the role of TLR4 in diabetic cardiomyopathy.

Does systemic delivery of TLR4 siRNA prevent or reduce diabetic cardiomyopathy in a mouse model of streptozotocin-induced type 1 diabetes?

Population

C57BL/6 mice with streptozotocin-induced diabetes

Comparison

TLR4 siRNA vs scrambled siRNA

Design

Animal experimental study

Authors

YZYuwei ZhangSichuan UniversityYLYang LiZhejiang International Studies UniversityXHXuefang HuangSun Yat-sen University

Discussion

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Member takes

Overview

May support TLR4 as target in diabetic cardiomyopathy models; hypothesis-generating and should not change practice.

Structured PICO

Does systemic delivery of TLR4 siRNA prevent or reduce diabetic cardiomyopathy in a mouse model of streptozotocin-induced type 1 diabetes?

P
Population
Male adult C57BL/6 mice, aged 6 to 8 weeks, with streptozotocin (STZ)-induced type 1 diabetes (n=30) and non-diabetic controls (n=10). Total n=40. Key inclusion: fasting blood glucose ≥16.7 mM at 72 h after STZ injections.
I
Intervention
5 μg of TLR4 small interfering RNA (siRNA) mixed with nanoparticle transfection reagent, administered intravenously via tail vein, repeated 4 weeks after the first treatment.
C
Comparator
5 μg of scrambled siRNA or untreated (sham).
O
Outcome
Myocardial function evaluated by echocardiography (fractional shortening and ejection fraction) and cardiac histopathology (hypertrophy, fibrosis, inflammation) at 8 weeks after treatment.surrogate

Main Result

Absolute Event Rate: 57.95% vs 45.34%

p-value: p=<0.05

Systemic silencing of the TLR4 gene using siRNA attenuates cardiac hypertrophy, fibrosis, inflammation, and myocardial dysfunction in a mouse model of type 1 diabetes.

Limitations

  • The major obstacle in clinical application of siRNA lies in developing safe and effective methods of delivering siRNA to target cells

Cite This Study

Zhang et al. (2020) studied Diabetic cardiomyopathy (n=40). TLR4 siRNA vs. Scrambled siRNA was evaluated on Ejection fraction (EF) (p=<0.05). Systemic delivery of TLR4 siRNA significantly preserved left ventricular ejection fraction (57.95% vs. 45.34%) and reduced hypertrophy, fibrosis, and inflammation in a mouse model of diabetic cardiomyopathy.

synapsesocial.com/papers/6a1ac0fc7ff99bba06461fd7https://doi.org/10.1007/s13300-020-00802-4
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Diabetic cardiomyopathy: mechanisms, diagnosis and treatment2004 · 353 citations
  2. 2Elevated plasma levels of TNF-alpha and Interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders2009 · 149 citations
  3. 3Impact of diabetes mellitus on long-term survival in patients with congestive heart failure2004 · 194 citations
  4. 4Diabetic Cardiomyopathy2006 · 572 citations
  5. 5Shikonin improve sepsis‐induced lung injury via regulation of miRNA‐140‐5p/TLR4—a vitro and vivo study2019 · 40 citations