Duchenne muscular dystrophy (DMD) is a severe muscle disease caused by mutations in the dystrophin gene. We have found that hematopoietic prostaglandin (PG) D synthase (HPGDS) was induced in grouped necrotic muscle fibers in DMD patients and also in model mice (mdx). DMD also affects cardiac muscle and cardiac failures are the most common causes of death in DMD patients. In this study, we developed a novel specific degrader for HPGDS protein composed of the HPGDS inhibitor and E3 ligase ligand and investigated beneficial role of HPGDS degradation to cardiac function and morphology in heart of mdx mice.
Dilated cardiomyopathy was induced in mdx mice by thyroid hormone [3,3‘,5-triiodo-L-thyronine (T3)]. T3 was daily injected subcutaneously in mdx mice for 2 weeks. HPGDS specific degrader was daily administered in T3-treated mdx mice. Serum cardiac troponin I and mRNAs of inflammatory cytokines in heart were measured. The severity of cardiomyopathy or fibrosis was histochemically evaluated.
mRNA of HPGDS, cyclooxygenases and prostanoid DP receptors were significantly upregulated after T3-treatment. In HPGDS specific degrader administrated T3-treated mdx, the hypertrophy of heart was significantly reduced compared to the vehicle-treated. HPGDS specific degrader treatment lowered the serum cardiac troponin I, prevented the expression of inflammatory cytokines, and decelerated the progression of fibrosis.
PGD₂ inhibition by HPGDS degradation prevents the progression of dilated cardiomyopathy in DMD mice.