LOSS OF ENDOTHELIAL CELL-SPECIFIC INTRAFLAGELLAR TRANSPORT PROTEIN 88 ENHANCES DOXORUBICIN-INDUCED CARDIOTOXICITY-RELATED PHENOTYPES
Canadian Journal of Cardiology(2019)
摘要
Doxorubicin (DOX) is an antineoplastic agent that is frequently prescribed for the treatment of solid tumours and hematologic malignancies. Prolonged exposure and incremental doses of DOX can cause cardiotoxicity culminating in myocardial remodeling and myocardial dysfunction. Whether the salutary and detrimental effects of DOX share the same underlying mechanisms remains unresolved although cumulative evidence implicate endothelial primary cilia as a potential protective gateway against DOX-associated cardiotoxicity. Accordingly, we hypothesized that DOX-mediated cardiac damage is enhanced in the absence of functional endothelial primary cilia. Inasmuch as the intraflagellar transport 88 (IFT88) gene is fundamental to cilia formation, we generated endothelial cell (EC)-specific IFT88 knockout (EC-IFT88-/-) mice to determine if EC primary cilia are involved in regulating cardiac function and survivability. Male 8-10 weeks EC-IFT88-/- mice and their wild type (WT) littermates, injected with either DOX (20 mg/kg i.p.) or an equivolume of saline, were randomized to three study groups. Survivability was monitored for up to 10 days and analyzed with the Kaplan-Meier estimator. Left ventricular function was evaluated via echocardiography performed at baseline, 2 days and 4 days post-DOX administration. Cardiac injury was determined through assessment of ventricular vacuolization, a well recognized surrogate measure of cardiomyocyte damage. Compared to their DOX-treated WT counterparts, DOX-treated EC-IFT88-/- mice showed significantly earlier mortality (Figure Panel A, 9.3 [0.9] days vs. 4.7 [0.9] days, respectively; P < 0.05). Echocardiography examination revealed that at baseline, left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) were similar in WT and EC-IFT88-/- mice (Figure Panels B and C). At 4 days post-DOX treatment, EC-IFT88-/- mice displayed significantly lower LVEF and LVFS (P < 0.05 for both) compared to the corresponding WT mice. The extent of ventricular vacuolization was independent of genotype amongst the hearts of saline-treated mice. Conversely, the ventricular cardiomyocytes of DOX-treated EC-IFT88-/- mice exhibited significantly greater vacuolization (131 [6.1] vacuoles/mm2) relative to those of DOX-treated WT mice (71 [11.1] vacuoles/mm2; P < 0.05). Loss of EC-specific IFT88 expression decreased the survival of DOX-treated mice. This phenomenon was in part due to the deterioration of left ventricular function. Further studies focused on evaluating the potential protective nature EC primary cilia on DOX-induced cardiotoxicity are warranted to provide further insights on the relationship between endothelial and myocardial health.
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关键词
cell-specific,doxorubicin-induced,cardiotoxicity-related
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