ANGPTL2 aggravates doxorubicin-induced cardiotoxicity via inhibiting DUSP1 pathway

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Toxicology

Background:

• Angiopoietin-like protein 2 (ANGPTL2) has diverse roles in cardiovascular diseases.
• The specific role of ANGPTL2 in doxorubicin (DOX)-induced cardiomyopathy is not well understood.

Purpose of the Study:

• To investigate the role of ANGPTL2 in the pathogenesis of DOX-related cardiomyopathy.
• To elucidate the underlying molecular mechanisms involving ANGPTL2 in cardiac injury.

Main Methods:

• Adeno-associated viral vectors were used for cardiac-specific overexpression and knockdown of ANGPTL2 in mice.
• Mice were treated with doxorubicin (DOX) to induce cardiomyopathy.
• Cardiac function was assessed using echocardiography and hemodynamic measurements.
• Molecular and biochemical assays were employed to analyze signaling pathways and cellular damage.

Main Results:

• DOX treatment significantly increased cardiac ANGPTL2 expression.
• ANGPTL2 overexpression exacerbated DOX-induced cardiac dysfunction, myocardial apoptosis, and oxidative stress.
• ANGPTL2 aggravated DOX cardiotoxicity by inhibiting the dual specificity phosphatase 1 (DUSP1) pathway.
• DUSP1 overexpression attenuated DOX-induced cardiomyopathy in mice with ANGPTL2 overexpression.

Conclusions:

• ANGPTL2 plays a detrimental role in DOX-related cardiomyopathy.
• The ANGPTL2-mediated exacerbation of cardiac injury involves the suppression of the DUSP1 pathway.
• Targeting the ANGPTL2/DUSP1 axis may offer a therapeutic strategy for preventing DOX-induced cardiotoxicity.