Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, 399 Royal Parade, Parkville, VIC, 3052, Australia.
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia.
Cardiovasc Diabetol. 2021 Jun 1;20(1):116. doi: 10.1186/s12933-021-01303-9.
Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart.
Diabetes was induced in male FVB/N mice by low-dose streptozotocin and a high-fat diet for 26-weeks. Cardiac function was measured by echocardiography at endpoint. Flow cytometry was performed on cardiac ventricles as well as blood, spleen, and bone-marrow at endpoint from non-diabetic and diabetic mice. To validate flow cytometry results, immunofluorescence staining was conducted on left-ventricles of age-matched mice.
Mice with diabetes exhibited hyperglycaemia and impaired glucose tolerance at endpoint. Echocardiography revealed reduced E:A and e':a' ratios in diabetic mice indicating diastolic dysfunction. Systolic function was not different between the experimental groups. Detailed examination of cardiac cellularity found resident mesenchymal cells (RMCs) were elevated as a result of diabetes, due to a marked increase in cardiac fibroblasts, while smooth muscle cells were reduced in proportion. Moreover, we found increased levels of Ly6C monocytes in both the heart and in the blood. Consistent with this, the proportion of bone-marrow haematopoietic stem cells were increased in diabetic mice.
Murine diabetes results in distinct changes in cardiac cellularity. These changes-in particular increased levels of fibroblasts-offer a framework for understanding how cardiac cellularity changes in diabetes. The results also point to new cellular mechanisms in this context, which may further aid in development of pharmacotherapies to allay the progression of cardiomyopathy associated with diabetes.
糖尿病与心血管疾病风险显著升高相关，但其特定的病理生理学仍不清楚。最近的研究改变了我们对心脏细胞性的认识，然而，糖尿病相关的细胞变化尚未得到详细研究。本研究旨在描述糖尿病小鼠心脏细胞景观的变化，以确定糖尿病心脏中的潜在细胞主角。
通过低剂量链脲佐菌素和高脂肪饮食诱导雄性 FVB/N 小鼠发生糖尿病，26 周后进行终点超声心动图检查。终点时对非糖尿病和糖尿病小鼠的心脏心室以及血液、脾脏和骨髓进行流式细胞术分析。为了验证流式细胞术结果，对年龄匹配的小鼠的左心室进行免疫荧光染色。
糖尿病小鼠在终点时出现高血糖和葡萄糖耐量受损。超声心动图显示糖尿病小鼠的 E:A 和 e':a' 比值降低，表明存在舒张功能障碍。实验组之间的收缩功能没有差异。对心脏细胞性的详细检查发现，由于心脏成纤维细胞的显著增加，驻留间充质细胞（RMCs）升高，而平滑肌细胞的比例降低。此外，我们还发现心脏和血液中的 Ly6C 单核细胞水平升高。与此一致的是，糖尿病小鼠的骨髓造血干细胞比例增加。
小鼠糖尿病导致心脏细胞性的明显变化。这些变化，特别是成纤维细胞水平的升高，为理解糖尿病中心脏细胞性变化提供了框架。研究结果还表明，在这种情况下存在新的细胞机制，这可能有助于开发药物治疗以减轻与糖尿病相关的心肌病的进展。
