ORCID

https://orcid.org/0000-0002-1545-0026

Keywords

Adverse remodeling, Cardiac dysfunction, Cardio-oncology, Cardioprotection, Cell death, Inflammation.

Abstract

Ponatinib (PON) is a third-generation tyrosine kinase inhibitor used to treat leukemia patients harboring the T315I mutation; however, its clinical use is limited by severe cardiotoxicity. The underlying mechanisms remain poorly defined, and no effective therapeutic strategies are currently available. In this study, we investigated the dual contribution of apoptosis and pyroptosis to PON-induced cardiotoxicity and evaluated whether Bone Morphogenetic Protein 7 (BMP-7), an FDA-approved growth factor for bone regeneration, could be repurposed as a cardioprotective agent. C57BL/6J mice received saline as a control or ponatinib (25 mg/kg cumulative dose), administered either alone or in combination with BMP-7 (600 μg/kg cumulative dose). Cardiac function was assessed by echocardiography, and cardiac tissues were analyzed using immunohistochemistry, Western blotting, ELISA, RT-PCR, and histological methods. PON induced cardiotoxicity by activating the intrinsic apoptotic pathway through dysregulation of the PTEN/Akt axis. This was associated with cardiomyocyte apoptosis, myocardial hypertrophy, fibrosis, and impaired ventricular function. BMP-7 treatment mitigated these effects by restoring Akt signaling, reducing apoptosis, and improving cardiac structure and function. Additionally, PON increased cardiac inflammation and triggered pyroptotic cell death, alongside activation of the TGF-β/SMAD signaling pathway. BMP-7 attenuated these inflammatory responses by inhibiting TGF-β/SMAD signaling. Overall, these findings demonstrate that PON-induced cardiotoxicity involves interconnected apoptotic and pyroptotic mechanisms. Importantly, BMP-7 effectively counteracted these effects, highlighting its potential as a therapeutic strategy to preserve cardiac function during PON treatment.

Completion Date

2026

Semester

Spring

Committee Chair

Dinender K. Singla

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Document Type

Thesis

Identifier

DP0053176

Release Date

5-15-2028

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Available for download on Monday, May 15, 2028

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