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Dapagliflozin protects against dilated cardiomyopathy progression by targeting NLRP3 inflammasome activation

Jiaxin Hu1,2, Jiamin Xu2, Xi Tan3

  • 1Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, No.158 Wuyang Avenue, Enshi, 445000, Hubei, China.

Naunyn-Schmiedeberg'S Archives of Pharmacology
|February 7, 2023
PubMed

Insights

Sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin show promise in treating dilated cardiomyopathy (DCM). Dapagliflozin improved cardiac function and reduced inflammation by inhibiting the NLRP3 inflammasome pathway in a doxorubicin-induced DCM mouse model.

Area of Science:

  • Cardiology
  • Pharmacology
  • Immunology

Background:

  • Dilated cardiomyopathy (DCM) is a primary cause of heart failure with a poor prognosis.
  • Inflammation plays a critical role in the pathogenesis of DCM.
  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer cardiac benefits in heart failure, but their specific role in DCM is not well-defined.

Purpose of the Study:

  • To investigate the therapeutic effect of the SGLT2 inhibitor dapagliflozin (Dapa) on doxorubicin (Dox)-induced dilated cardiomyopathy (DCM) in a mouse model.
  • To elucidate the underlying mechanisms, focusing on the nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome pathway.

Main Methods:

  • Establishment of a doxorubicin (Dox)-induced mouse model of dilated cardiomyopathy (DCM).
  • Administration of the SGLT2 inhibitor dapagliflozin (Dapa) to Dox-treated mice.
  • Assessment of cardiac function, NLRP3 inflammasome activation, inflammatory factor expression, and the role of p38-dependent toll-like receptor 4 (TLR4) signaling.

Main Results:

  • Dapagliflozin treatment significantly improved cardiac function in mice with doxorubicin-induced DCM.
  • Dapagliflozin attenuated the activation of the NLRP3 inflammasome pathway and reduced the expression of key inflammatory factors.
  • Dapagliflozin was found to suppress NLRP3 activation by decreasing p38-dependent toll-like receptor 4 (TLR4) expression.

Conclusions:

  • Dapagliflozin demonstrates a protective effect in a mouse model of dilated cardiomyopathy (DCM).
  • The cardioprotective mechanism involves the inhibition of the NLRP3 inflammasome pathway.
  • Targeting the NLRP3 inflammasome via SGLT2 inhibition represents a potential therapeutic strategy for DCM.
Keywords:
Dilated cardiomyopathyInflammationNLRP3 inflammasomeSGLT2 inhibitorsTLR4

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