[No authors listed]
AIMS:Age-related cardiac hypertrophy and subsequent heart failure are predicted to become increasingly serious problems in aging populations. Progranulin (PGRN) deficiency is known to be associated with accelerated aging in the brain. We aimed to evaluate the effects of PGRN deficiency on cardiac aging, including left ventricular hypertrophy. METHODS AND RESULTS:Echocardiography was performed on wild-type (WT) and PGRN-knockout (KO) mice every 3 months from 3 to 18 months of age. Compared to that of WT mice, PGRN KO mice exhibited age-dependent cardiac hypertrophy and cardiac dysfunction at 18 months. Morphological analyses showed that the heart weight to tibia length ratio and cross-sectional area of cardiomyocytes at 18 months were significantly increased in PGRN KO mice relative to those in WT mice. Furthermore, accumulation of lipofuscin and increases in senescence markers were observed in the hearts of PGRN KO mice, suggesting that PGRN deficiency led to enhanced aging of the heart. Enhanced complement C1q (C1q) and activated β-catenin protein expression levels were also observed in the hearts of aged PGRN KO mice. Treatment of PGRN-deficient cardiomyocytes with C1q caused β-catenin activation and cardiac hypertrophy. Blocking C1q-induced β-catenin activation in PGRN-depleted cardiomyocytes attenuated hypertrophic changes. Finally, we showed that C1 inhibitor treatment reduced cardiac hypertrophy and dysfunction in old KO mice, possibly by reducing β-catenin activation. These results suggest that C1q is a crucial regulator of cardiac hypertrophy induced by PGRN ablation. CONCLUSION:The present study demonstrates that PGRN deficiency enhances age-related cardiac hypertrophy via C1q-induced β-catenin activation. PGRN is a potential therapeutic target to prevent cardiac hypertrophy and dysfunction.
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