Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China; Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
Transl Res. 2019 Jun;208:1-14. doi: 10.1016/j.trsl.2019.01.005. Epub 2019 Jan 19.
Mast cells (MCs) have been implicated in the pathogenesis of cardiometabolic diseases by releasing pro-inflammatory mediators. Patients and animals with diabetic cardiomyopathy (DCM) also show inflammatory cell accumulation in the heart. Here, we detected MCs in mouse heart after streptozotocin (STZ)-induced DCM. DCM production caused significant systole and diastole interventricular septum and left ventricular (LV) posterior wall thinning, and systolic LV internal dilation in wild-type (WT) mice. DCM production also led to significant reductions of fractional shortening percentage, heart rate, body weight, heart weight, and significant increases of kidney, pancreas, and lung weight to body weight ratios, and blood hemoglobin HbA1c and glucose levels in WT mice. All these changes were improved or disappeared in MC-deficient Kit mice. In the myocardium from WT DCM mice, we detected significant decrease of cardiac cell proliferation and increases of cardiac cell death, chemokine expression, macrophage infiltration, inflammatory cytokine expression, and collagen deposition. These changes were also improved or disappeared in Kit DCM mice. Adoptive transfer of bone marrow-derived MCs (BMMCs) from WT mice fully or partially reversed these cardiac functional and morphologic changes in Kit DCM recipient mice. Yet, adoptive transfer of BMMCs from Il6 and Tnf mice failed to make these corrections or at much less extent than the WT BMMCs. Mechanistic studies demonstrated a role of MC and MC-derived IL6 and TNF-α in promoting cardiomyocyte death and cardiac fibroblast TGF-β signaling, and collagen synthesis and deposition. Therefore, MC inhibition may have therapeutic potential in attenuating DCM progression.
肥大细胞（MCs）通过释放促炎介质参与了心脏代谢疾病的发病机制。患有糖尿病心肌病（DCM）的患者和动物也显示心脏中有炎症细胞积聚。在这里，我们在链脲佐菌素（STZ）诱导的 DCM 后检测到了小鼠心脏中的 MCs。DCM 的产生导致 WT 小鼠的收缩期和舒张期室间隔和左心室（LV）后壁变薄，以及 LV 内部收缩期扩张显著。DCM 的产生还导致 WT 小鼠的缩短分数百分比、心率、体重、心脏重量显著降低，以及肾脏、胰腺和肺重量与体重比显著增加，血红蛋白 HbA1c 和血糖水平显著升高。所有这些变化在 MC 缺陷 Kit 小鼠中都得到了改善或消失。在 WT DCM 小鼠的心肌中，我们检测到心脏细胞增殖显著减少，细胞死亡、趋化因子表达、巨噬细胞浸润、炎症细胞因子表达和胶原沉积增加。在 Kit DCM 小鼠中，这些变化也得到了改善或消失。从 WT 小鼠中过继转移骨髓来源的 MCs（BMMCs）完全或部分逆转了 Kit DCM 受体小鼠的心脏功能和形态变化。然而，从 Il6 和 Tnf 小鼠中过继转移的 BMMCs 未能进行这些纠正，或者程度远低于 WT BMMCs。机制研究表明 MC 及其衍生的 IL6 和 TNF-α 在促进心肌细胞死亡和心脏成纤维细胞 TGF-β 信号转导以及胶原合成和沉积中起作用。因此，MC 抑制可能在减轻 DCM 进展方面具有治疗潜力。
