The Wilf Family Cardiovascular Research Institute Department of Medicine (Cardiology), Albert Einstein College of Medicine Bronx NY.
J Am Heart Assoc. 2023 Mar 21;12(6):e027463. doi: 10.1161/JAHA.122.027463. Epub 2023 Mar 9.
Background Interstitial and perivascular fibrosis may contribute to diabetes-associated heart failure. Pericytes can convert to fibroblasts under conditions of stress and have been implicated in the pathogenesis of fibrotic diseases. We hypothesized that in diabetic hearts, pericytes may convert to fibroblasts, contributing to fibrosis and to the development of diastolic dysfunction. Methods and Results Using pericyte:fibroblast dual reporter (NG2 [neuron-glial antigen 2 red fluorescent protein variant]; PDGFRα [platelet-derived growth factor receptor alpha enhanced green fluorescent protein]) mice in a type 2 diabetic db/db background, we found that diabetes does not significantly affect pericyte density but reduces the myocardial pericyte:fibroblast ratio. Lineage tracing using the inducible NG2 driver, along with reliable labeling of fibroblasts with the PDGFRα reporter system, showed no significant pericyte to fibroblast conversion in lean and db/db hearts. In addition, db/db mouse cardiac fibroblasts did not undergo myofibroblast conversion and had no significant induction of structural collagens but exhibited a matrix-preserving phenotype, associated with increased expression of antiproteases, matricellular genes, matrix cross-linking enzymes, and the fibrogenic transcription factor . In contrast, db/db mouse cardiac pericytes had increased expression of , without any changes in expression of other fibrosis-associated genes. The matrix-preserving phenotype of diabetic fibroblasts was associated with induction of genes encoding oxidative (/cycloxygenase-2, and ) and antioxidant proteins (, ). In vitro, high glucose partially recapitulated the in vivo changes in diabetic fibroblasts. Conclusions Diabetic fibrosis is not mediated through pericyte to fibroblast conversion but involves acquisition of a matrix-preserving fibroblast program, which is independent of myofibroblast conversion and is only partially explained by the effects of the hyperglycemic environment.
间质和血管周围纤维化可能导致与糖尿病相关的心力衰竭。在应激条件下，周细胞可以转化为成纤维细胞，并与纤维性疾病的发病机制有关。我们假设在糖尿病心脏中，周细胞可能转化为成纤维细胞，导致纤维化和舒张功能障碍的发展。
使用周细胞：成纤维细胞双重报告（NG2[神经元-神经胶质抗原 2 红色荧光蛋白变体]；PDGFRα[血小板衍生生长因子受体α 增强型绿色荧光蛋白]）在 2 型糖尿病 db/db 背景下的小鼠，我们发现糖尿病对周细胞密度没有显著影响，但降低了心肌周细胞：成纤维细胞比值。使用可诱导的 NG2 驱动子进行谱系追踪，以及使用 PDGFRα 报告系统可靠地标记成纤维细胞，显示在瘦鼠和 db/db 心脏中没有明显的周细胞向成纤维细胞转化。此外，db/db 小鼠心脏成纤维细胞没有发生肌成纤维细胞转化，没有显著诱导结构胶原，但表现出基质保留表型，与抗蛋白酶、基质细胞基因、基质交联酶和纤维生成转录因子 的表达增加有关。相比之下，db/db 小鼠心脏周细胞 表达增加，但与其他纤维化相关基因的表达没有变化。糖尿病成纤维细胞的基质保留表型与编码氧化酶（/环氧化酶-2 和 ）和抗氧化蛋白（、）的基因的诱导有关。在体外，高葡萄糖部分再现了糖尿病成纤维细胞的体内变化。
糖尿病纤维化不是通过周细胞向成纤维细胞转化介导的，而是涉及获得基质保留的成纤维细胞程序，该程序独立于肌成纤维细胞转化，并且仅部分由高血糖环境的影响解释。
