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PDE1 Inhibition Attenuates Doxorubicin‐Induced Toxicity in Primary Mouse Cardiomyocytes
Author(s) -
Vigneshwar Navin,
Samidurai Arun,
Movsesian Matthew,
Das Anindita,
Kukreja Rakesh C
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.817.12
Subject(s) - cardiotoxicity , apoptosis , doxorubicin , tunel assay , pharmacology , trypan blue , necrosis , programmed cell death , phosphodiesterase , chemistry , medicine , toxicity , biochemistry , chemotherapy , enzyme
Background Doxorubicin (DOX) is a widely used and effective chemotherapeutic agent, but is associated with a delayed and progressive cardiomyopathy. Phosphodiesterase 5 (PDE5) inhibitors have been shown to be protective of heart function with DOX co‐treatment in animal models, but PDE5 is expressed at low levels in human heart. In contrast, phosphodiesterase 1 (PDE1) comprises a large fraction of the cGMP‐hydrolytic activity in both human and mouse heart. We hypothesized that PDE1 inhibition would be protect against DOX cardiotoxicity by improving cell survival (cGMP effect) and eliciting inotropic response (a cAMP effect). Methods and Results Isolated cardiomyocytes from adult male C57BL/6J mouse were treated with DOX (1 μM) and/or a quinazoline‐based PDE1‐selective inhibitor (5 μM) for 24 hours. Necrosis and apoptosis were assessed by trypan blue staining and TUNEL assay, respectively. Mitochondrial membrane potential (ΔΨm) was evaluated by JC‐1 staining. DOX treatment increased cardiomyocyte necrosis, apoptosis and caused loss of ΔΨm. Treatment with PDE1 inhibitor in combination with DOX significantly (P<0.05) reduced necrosis (37.4±3.9 vs 60.2±4.1% DOX alone, n=6; Figure 1A), apoptosis (17.3±1.22 vs 39.6±2.4% DOX alone, n=8; Figure 1B) and improved ΔΨm (3.1±0.4 vs 0.98±0.01 with DOX alone, n=4; Figure 1C). Conclusion PDE1 inhibition has anti‐apoptotic and anti‐necrotic effects against DOX‐induced cardiomyocyte death. PDE1 inhibition in combination with DOX could potentially be an efficient therapeutic strategy to reduce DOX‐induced cardiotoxicity in cancer patients. Support or Funding Information R37HL0510454 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .