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Updated: May 5, 2026
A Simple and Efficient Method for In Vivo Cardiac-specific Gene Manipulation by Intramyocardial Injection in Mice
Published on: April 16, 2018
Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice
Naoki Nozaki1, Tetsuro Shishido, Yasuchika Takeishi
1First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
Background:
Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and are involved in the responsiveness to pathogen-associated molecular patterns. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, which may contribute to congestive heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction.
Methods And Results:
Cardiac dysfunction was induced by a single injection of Dox (20 mg/kg IP) into wild-type (WT) mice and TLR-2-knockout (KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice (P<0.01). Nuclear factor-kappaB activation and production of proinflammatory cytokines after Dox were suppressed in KO mice compared with WT mice (P<0.01). The numbers of TUNEL-positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice (P<0.01). Survival rate was significantly higher in KO mice than in WT mice 10 days after Dox injection (46% vs 11%, P<0.05).
Conclusions:
These findings suggest that TLR-2 may play a role in the regulation of inflammatory and apoptotic mediators in the heart after Dox administration.
Insights
Toll-like receptor-2 (TLR-2) activation exacerbates doxorubicin-induced cardiac dysfunction by promoting inflammation and apoptosis. Blocking TLR-2 in mice significantly improved cardiac function and survival rates following doxorubicin treatment.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Toll-like receptors (TLRs) are implicated in inflammatory responses and may contribute to heart failure.
- Oxidative stress, a key factor in doxorubicin (Dox)-induced cardiac dysfunction, can activate TLRs.
- Endogenous signals like heat shock proteins and oxidative stress activate TLRs.
Purpose of the Study:
- To investigate the role of TLRs in the pathogenesis of doxorubicin-induced cardiac dysfunction.
- To determine if TLR-2 knockout (KO) mice exhibit altered cardiac function and survival after doxorubicin administration.
Main Methods:
- Cardiac dysfunction was induced in wild-type (WT) and TLR-2 KO mice using a single injection of doxorubicin (20 mg/kg).
- Cardiac function, including left ventricular dimension and fractional shortening, was assessed.
- Inflammatory markers (NF-κB activation, pro-inflammatory cytokines), apoptosis (TUNEL, caspase-3), and survival rates were evaluated.
Main Results:
- TLR-2 KO mice showed improved cardiac function compared to WT mice post-doxorubicin treatment.
- NF-κB activation and pro-inflammatory cytokine production were suppressed in TLR-2 KO mice.
- Apoptosis markers and caspase-3 activation were reduced in TLR-2 KO mice.
- Survival rates were significantly higher in TLR-2 KO mice (46%) versus WT mice (11%) 10 days after doxorubicin injection.
Conclusions:
- TLR-2 plays a significant role in mediating cardiac inflammation and apoptosis following doxorubicin administration.
- Targeting TLR-2 may offer a therapeutic strategy to mitigate doxorubicin-induced cardiotoxicity.
