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.

中文翻译：

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前体颗粒蛋白缺乏症通过补体C1q诱导的β-catenin活化导致与年龄相关的心脏肥大。

预计与年龄有关的心脏肥大和随后的心力衰竭将在老年人口中成为越来越严重的问题。众所周知，前颗粒蛋白（PGRN）缺乏与大脑加速衰老有关。我们旨在评估PGRN缺乏症对心脏衰老（包括左心室肥大）的影响。方法和结果从3到18个月大时，每3个月对野生型（WT）和PGRN敲除（KO）小鼠进行超声心动图检查。与WT小鼠相比，PGRN KO小鼠在18个月时表现出年龄依赖性心脏肥大和心脏功能障碍。形态学分析表明，与野生型小鼠相比，PGRN KO小鼠在18个月时的心重/胫骨长度比和心肌细胞的横截面积显着增加。此外，在PGRN KO小鼠的心脏中观察到脂褐素的积累和衰老标记的增加，这表明PGRN缺乏导致了心脏衰老的加剧。在老年PGRN KO小鼠的心脏中也观察到增强的补体C1q（C1q）和活化的β-catenin蛋白表达水平。用C1q处理PGRN缺陷型心肌细胞会导致β-catenin活化和心肌肥大。在PGRN耗尽的心肌细胞中阻断C1q诱导的β-catenin激活可减弱肥厚性改变。最后，我们表明，C1抑制剂治疗可通过降低β-catenin活化来减轻老年KO小鼠的心脏肥大和功能障碍。这些结果表明，C1q是由PGRN消融诱导的心脏肥大的重要调节剂。结论本研究表明，PGRN缺乏可通过C1q诱导的β-catenin活化增强与年龄有关的心脏肥大。PGRN是预防心脏肥大和功能障碍的潜在治疗靶标。