Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib

Area of Science:

• Cardiovascular Biology
• Cancer Therapeutics
• Cellular Autophagy

Background:

• Excessive autophagy contributes to cardiomyocyte death in cardiovascular diseases and cancer therapy.
• Sunitinib, a common anti-cancer drug, has been implicated in autophagy-related cardiomyocyte death.
• The precise mechanisms underlying sunitinib-induced cardiotoxicity via autophagy require elucidation.

Purpose of the Study:

• To investigate the mechanism of sunitinib-induced cardiomyocyte death mediated by autophagy.
• To identify key molecular players involved in sunitinib-induced cardiotoxicity.
• To explore potential therapeutic strategies to mitigate sunitinib-induced cardiac damage.

Main Methods:

• Utilized cardiomyocyte-specific Atg7 heterozygous mice to assess sunitinib effects.
• Investigated the role of CCN2 (cellular communication network factor 2) degradation in sunitinib cardiotoxicity.
• Employed adeno-associated virus serotype 9 (AAV9) for cardiomyocyte-specific Ccn2 knockdown in vivo.
• Examined the impact of Hmgb1 deletion and HMGB1 inhibition (glycyrrhizic acid) on sunitinib-induced autophagy and apoptosis.

Main Results:

• Sunitinib induces cardiomyocyte apoptosis and cardiac dysfunction, which is attenuated in Atg7 heterozygous mice.
• Maladaptive autophagy selectively degrades CCN2 via a TOLLIP-mediated pathway, leading to cardiac dysfunction.
• Ccn2 knockdown mimics sunitinib-induced cardiac dysfunction.
• Hmgb1 deletion and glycyrrhizic acid treatment inhibit sunitinib-induced autophagy, apoptosis, and cardiotoxicity.

Conclusions:

• Autophagic degradation of CCN2 is a key mechanism in sunitinib-induced cardiotoxicity.
• HMGB1 plays a critical role in mediating sunitinib-induced cardiomyocyte autophagy and death.
• Inhibiting HMGB1 presents a promising therapeutic strategy to enhance the safety of sunitinib-based cancer therapy.