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Compound c17 alleviates inflammatory cardiomyopathy in streptozotocin-induced diabetic mice by targeting MyD88
Qianhui Zhang1, Weiwei Zhu2, Shuaijie Lou3
1Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo 315700, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
Insights
A novel compound, c17, effectively treats diabetic cardiomyopathy (DCM) by inhibiting myeloid differentiation primary response 88 (MyD88). This reduces cardiac inflammation and improves heart function in diabetic mice.
Area of Science:
- Cardiology
- Pharmacology
- Immunology
Background:
- Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, leading to cardiac dysfunction and increased mortality.
- Chronic inflammation is a key driver of DCM development, presenting a therapeutic target.
- Previous research identified compound c17 as a potent anti-inflammatory agent targeting myeloid differentiation primary response 88 (MyD88).
Purpose of the Study:
- To evaluate the therapeutic efficacy of the novel compound c17 in a mouse model of diabetic cardiomyopathy.
- To investigate the anti-inflammatory mechanisms of c17 in the context of DCM.
Main Methods:
- Compound c17, a selective MyD88 inhibitor, was tested in streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice.
- In vitro studies utilized high glucose- and palmitic acid-stimulated macrophages.
- Cardiac function, hypertrophy, inflammation, and fibrogenesis were assessed. RNA sequencing and co-immunoprecipitation were employed.
Main Results:
- c17 treatment improved cardiac function and reduced hypertrophy, inflammation, and fibrogenesis in T1DM mice.
- RNA sequencing confirmed c17's suppression of inflammation via the MyD88-dependent pathway.
- c17 inhibited the MyD88-TLR4 interaction, blocking downstream NF-κB activation and reducing inflammatory effects on cardiomyocytes.
Conclusions:
- The small-molecule MyD88 inhibitor c17 demonstrates significant therapeutic potential for inflammatory DCM.
- c17 effectively targets key inflammatory pathways implicated in diabetic heart disease.
- c17 represents a promising candidate for future pharmacological interventions in DCM treatment.
Background:
Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and is associated with increased morbidity and mortality due to cardiac dysfunction. Chronic inflammation plays a significant role in the development of DCM, making it a promising target for novel pharmacological strategies. Our previous study has synthesized a novel compound, c17, which exhibited strong anti-inflammatory activity by specifically targeting to myeloid differentiation primary response 88 (MyD88). In this study, we evaluated the therapeutic effect of c17 in DCM.
Methods:
The small molecular selective MyD88 inhibitor, c17, was used to evaluate the effect of MyD88 on DCM in both high concentration of glucose- and palmitic acid-stimulated macrophages and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice.
Results:
The treatment of c17 in T1DM mice resulted in improved heart function and reduced cardiac hypertrophy, inflammation and fibrogenesis. RNA sequencing analysis of the heart tissues revealed that c17 effectively suppressed the inflammatory response by regulating the MyD88-dependent pathway. Co-immunoprecipitation experiments further confirmed that c17 disrupted the interaction between MyD88 and Toll-like receptor 4 (TLR4), consequently inhibiting downstream NF-κB activation. In vitro studies demonstrated that c17 exhibited similar anti-inflammatory activity by targeting MyD88 in macrophages, which are the primary regulators of cardiac inflammation. Furthermore, conditioned medium derived from c17-treated macrophages showed reduced capacity to induce hypertrophy, pro-fibrotic reactions, and secondary inflammation in cardiomyocytes.
Conclusions:
In conclusion, the small-molecule MyD88 inhibitor, c17, effectively combated the inflammatory DCM, therefore could be a potential candidate for the treatment of this disease.
