Adenylate cyclase 1 knockdown attenuates pirarubicin-induced cardiotoxicity

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Pirarubicin (THP) is a chemotherapy drug known to cause cardiotoxicity.
• The precise mechanisms underlying THP-induced cardiomyocyte injury are not fully understood.
• Adenylate cyclase 1 (ADCY1) is an enzyme implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of ADCY1 in pirarubicin (THP)-induced damage to mouse cardiomyocytes.
• To elucidate the molecular mechanisms by which ADCY1 influences THP cardiotoxicity.

Main Methods:

• HL-1 cells were treated with THP to induce cardiotoxicity.
• Cell viability, proliferation, apoptosis, and oxidative stress were assessed using CCK-8, Edu, flow cytometry, and ROS assays.
• Gene and protein expression levels of ADCY1, PKA, and GRIN2D were analyzed by RT-qPCR and Western blotting.
• Molecular docking was used to predict interactions between ADCY1 and THP.

Main Results:

• THP treatment significantly reduced HL-1 cell viability, inhibited proliferation, induced apoptosis, and increased oxidative stress.
• ADCY1 expression was significantly upregulated in THP-treated cells.
• Molecular docking suggested a direct interaction between ADCY1 and THP.
• Elevated levels of ADCY1, phospho-protein kinase A (p-PKA), and GRIN2D were observed.
• Knockdown of ADCY1 attenuated THP-induced cardiotoxicity.

Conclusions:

• ADCY1 is involved in pirarubicin-induced cardiotoxicity.
• The ADCY1/PKA/GRIN2D pathway appears to mediate THP-induced cardiomyocyte injury.
• Targeting ADCY1 may offer a therapeutic strategy to mitigate pirarubicin cardiotoxicity.