Division of Nanomedicine and Molecular Intervention, Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, Michigan, United States of America.
PLoS One. 2022 Sep 14;17(9):e0274618. doi: 10.1371/journal.pone.0274618. eCollection 2022.
Age-related cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction which lacks ideal treatment. Transient receptor potential ankyrin 1 (TRPA1) is an oxidative stress sensor and could attenuate age-related pathologies in invertebrates. The present study aimed to test whether TRPA1 plays a role in age-related cardiac remodeling and dysfunction. The cardiac function and pathology of 12-week-old (young) and 52-week-old (older) Trpa1-/- mice and wild-type (WT) littermates were evaluated by echocardiography and histologic analyses. The expression levels of 84 fibrosis-related genes in the heart were measured by quantitative polymerase chain reaction array. Young Trpa1-/- and WT mice had similar left ventricular wall thickness, volume, and systolic and diastolic function. Older Trpa1-/- mice had significantly increased left ventricular internal diameter and volume and impaired systolic (lower left ventricular ejection fraction) and diastolic (higher E/A ratio and isovolumetric relaxation time) functions compared with older WT mice (P<0.05 or P<0.01). Importantly, older Trpa1-/- mice had enhanced cardiac fibrosis than older WT mice (P<0.05) while the two strains had similar degree of cardiac hypertrophy. Among the 84 fibrosis-related genes, Acta2, Inhbe, Ifng, and Ccl11 were significantly upregulated, while Timp3, Stat6, and Ilk were significantly downregulated in the heart of older Trpa1-/- mice compared with older WT mice. Taken together, we found that knocking out Trpa1 accelerated age-related myocardial fibrosis, ventricular dilation, and cardiac dysfunction. These findings suggest that TRPA1 may become a therapeutic target for preventing and/or treating cardiac fibrosis and heart failure with preserved ejection fraction in the elderly.
年龄相关性心肌纤维化导致射血分数保留型心力衰竭的发生，而后者缺乏理想的治疗方法。瞬时受体电位锚蛋白 1（TRPA1）是一种氧化应激传感器，可减轻无脊椎动物的年龄相关病变。本研究旨在测试 TRPA1 是否在年龄相关性心脏重塑和功能障碍中发挥作用。通过超声心动图和组织学分析评估 12 周龄（年轻）和 52 周龄（年老）Trpa1-/- 小鼠和野生型（WT）同窝仔鼠的心脏功能和病理。通过定量聚合酶链反应阵列测量心脏中 84 个纤维化相关基因的表达水平。年轻的 Trpa1-/- 和 WT 小鼠的左心室壁厚度、容积和收缩及舒张功能相似。与年老的 WT 小鼠相比，年老的 Trpa1-/- 小鼠的左心室内径和容积显著增加，收缩功能（左心室射血分数降低）和舒张功能（E/A 比值升高和等容舒张时间延长）受损（P<0.05 或 P<0.01）。重要的是，年老的 Trpa1-/- 小鼠的心脏纤维化程度高于年老的 WT 小鼠（P<0.05），而两株小鼠的心脏肥大程度相似。在 84 个纤维化相关基因中，Acta2、Inhbe、Ifng 和 Ccl11 显著上调，而 Timp3、Stat6 和 Ilk 显著下调。综上所述，我们发现敲除 Trpa1 加速了年龄相关性心肌纤维化、心室扩张和心功能障碍。这些发现表明，TRPA1 可能成为预防和/或治疗老年人心肌纤维化和射血分数保留型心力衰竭的治疗靶点。
