Figure 8. A₂R activation mediates the protective effect of PDE1C deficiency against doxorubicin-induced cardiac toxicity in vivo.

Male or female PDE1C-WT or PDE1C-KO mice were treated with doxorubicin (DOX, 20 mg/kg, i.p.) in a single bolus via i.p., and also pretreated with ZM241385 (10 mg/kg/day) and/or vehicle via i.p. 2 days before DOX and continued for additional 5 days. (A) Representative images of whole hearts and cross sections with H&E staining. Scale bars: 1 mm. (B) Quantification of heart weight/tibia length. (C) Representative image of heart sections with TUNEL staining. White arrows point to TUNEL positive apoptotic cardiomyocytes. Scale bars: 50 μm. (D) Quantification of TUNEL staining results. (E) Fractional shortening assessed by echocardiography at the time of termination. (F) Plasma troponin I (cTnI) levels. Data are presented as mean ± SEM. *p<0.05 by one-way ANOVA with Bonferroni’s correction. B, D, E, and F: n= 3–5 for male mice and n=3–5 for female mice. (G) Proposed model. Pathological stimuli, such as Ang II or DOX, activate TRPC3 and result in Ca²⁺ influx. This serves to activate PDE1C and subsequently increases the degradation of cAMP derived from A₂R activation, which promotes cell death.