Doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy
(A) Representative gross and microscopic pathology. Left column: Cross-sections of mouse hearts fixed at a constant intracavitary pressure illustrate DOX-induced cardiomyopathy after 14 days. Normal mouse heart (control), CO control (CO), and DOX cross-sections are shown. CO administration, but not HH, preserves myocardial mass and LV wall thickness in DOX-treated mice. Middle column: Representative photomicrographs of LV sections of control, CO, DOX, and CO+DOX–treated mice stained with H&E (original magnification, ×250; scale bar = 10 μm). Normal myocardial morphology is shown (control). CO did not alter the myocardial morphology. DOX-damaged hearts showed extensive cytoplasmic vacuolization, myofibrillar loss, and cell death. Cardiomyocyte vacuolization and cell death were greatly reduced in animals that received CO, but swelling and vacuolization were still prominent after HH. Right column: Representative photomicrographs of mouse LV sections stained with Masson’s trichrome. Arrows indicate fibrosis of endomysium (light blue staining). Mice treated with CO showed less fibrosis after DOX. (B) Quantification of the interstitial fibrosis. Each bar represents mean ± SEM of 6 hearts. *P < 0.01 versus control; †P < 0.05 versus DOX. Note that CO protects, but HH does not.
The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy Hagir B. Suliman, Martha Sue Carraway, Abdelwahid S. Ali, Chrystal M. Reynolds, Karen E. Welty-Wolf, Claude A. PiantadosiPublished in Volume 117, Issue 12J Clin Invest. 2007; 117(12):3730 doi:10.1172/JCI32967