Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction
Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction
复制标题
DOI：
10.1152/ajpheart.00238.2018
复制
发表时间：
2018-10-01
影响因子：
4.8
通讯作者：
Frangogiannis, Nikolaos G.
中科院分区：
文献类型：
--
作者：
Alex, Linda;Russo, Ilaria;Frangogiannis, Nikolaos G.
射血分数保留性心力衰竭（HFpEF）是由以下原因引起或加重的。各种心外疾病糖尿病、肥胖和代谢功能障碍与独特的HFpEF表型相关，其特征在于炎症、心脏纤维化和微血管功能障碍。由于缺乏可靠的动物模型，HFpEF新疗法的开发受到阻碍。瘦素耐药db/db小鼠已被广泛研究作为糖尿病相关心肌病的模型;然而，db/db心脏的功能和形态学改变的数据是相互矛盾的。在本研究中，我们报告了db/db小鼠心脏表型的系统表征，重点是功能和组织病理学改变的时间过程和性别特异性细胞事件的识别。尽管雄性和雌性db/db小鼠均出现严重肥胖，但肥胖增加。和高血糖症。雌性小鼠的体重增加更令人印象深刻，血压也有适度但显著的增加。db/db小鼠具有肥厚性心室重塑和舒张功能障碍，射血分数保持不变：雌性小鼠左心室质量增加加重。组织学分析显示，雄性和雌性db/db小鼠均具有心肌细胞肥大和间质纤维化，与肌周胶原显著增厚相关。以及动脉周围胶原网络的扩张。在体内和体外实验表明，db/db心脏的纤维化变化与心脏成纤维细胞的胶原合成增加，在骨膜蛋白，α-平滑肌肌动蛋白，或成纤维细胞活化蛋白过表达的情况下。雄性db/db小鼠表现出微血管稀疏。总之，db/db小鼠模型概括了与代谢功能障碍相关的人HFpEF的功能和组织学特征。在db/db心脏纤维化的发展，在没有肌成纤维细胞转换，表明代谢功能障碍可能会激活一个替代的profibrotic途径与accentuated细胞外基质蛋白synthesis.NEW &值得注意的是，我们提供了一个系统的分析性别特异性功能和结构的db/db小鼠心肌的改变。肥胖糖尿病C57 BL 6 J db/db小鼠表现出舒张功能障碍，射血分数保持不变，与心肌细胞肥大、间质/血管周围纤维化和微血管稀疏相关。从而概括了具有保留射血分数的人肥胖相关心力衰竭的方面。db/db小鼠的心肌纤维化与基质生成成纤维细胞表型相关，在没有肌成纤维细胞转化的情况下，这表明了另一种激活机制。
Heart failure with preserved ejection fraction (HFpEF) is caused, or exacerbated by. a wide range of extracardiac conditions. Diabetes, obesity, and metabolic dysfunction arc associated with a unique HFpEF phenotype, characterized by inflammation, cardiac fibrosis, and microvascular dysfunction. Development of new therapies for HFpEF is hampered by the absence of reliable animal models. The leptin-resistant db/db mouse has been extensively studied as a model of diabetes-associated cardiomyopathy; however, data on the functional and morphological alterations in db/db hearts are conflicting. In the present study, we report a systematic characterization of the cardiac phenotype in db/db mice, focusing on the time course of functional and histopathological alterations and on the identification of sex-specific cellular events. Although both male and female db/db mice developed severe obesity, increased adiposity. and hyperglycemia. female mice had more impressive weight gain and exhibited a modest but significant increase in blood pressure. db/db mice had hypertrophic ventricular remodeling and diastolic dysfunction with preserved ejection fraction: the increase in left ventricular mass was accentuated in female mice. Histological analysis showed that both male and female db/db mice had cardiomyocyte hypertrophy and interstitial fibrosis, associated with marked thickening of the perimysial collagen. and expansion of the periarteriolar collagen network, in the absence of replacement fibrosis. In vivo and in vitro experiments showed that fibrotic changes in db/db hearts were associated with increased collagen synthesis by cardiac fibroblasts, in the absence of periostin, alpha-smooth muscle actin, or fibroblast activation protein overexpression. Male db/db mice exhibited microvascular rarefaction. In conclusion, the db/db mouse model recapitulates functional and histological features of human HFpEF associated with metabolic dysfunction. Development of fibrosis in db/db hearts, in the absence of myofibroblast conversion, suggests that metabolic dysfunction may activate an alternative profibrotic pathway associated with accentuated extracellular matrix protein synthesis.NEW & NOTEWORTHY We provide a systematic analysis of the sex-specific functional and structural myocardial alterations in db/db mice. Obese diabetic C57BL6J db/db mice exhibit diastolic dysfunction with preserved ejection fraction, associated with cardiomyocyte hypertrophy, interstitial/perivascular fibrosis, and microvascular rarefaction. thus recapitulating aspects of human obesity-related heart failure with preserved ejection fraction. Myocardial fibrosis in db/db mice is associated with a matrix-producing fibroblast phenotype, in the absence of myofibroblast conversion, suggesting an alternative mechanism of activation.