Abstract
BackgroundDiabetes 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.MethodsDiabetes 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.ResultsMice 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 Ly6Chi 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.ConclusionsMurine 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.
Highlights
Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear
The STZ‐HFD model recapitulates primary features of diabetes The presence of diabetes was confirmed by a range of physiological tests prior to euthanasia
Consistent with our previous report [17], mice with diabetes exhibited significantly elevated blood glucose at endpoint (Additional file 1: Table S1). This was corroborated by measurement of glycated haemoglobin (% H bA1c) at endpoint, which was significantly increased in mice with diabetes (P < 0.0001; Additional file 1: Table S1)
Summary
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 mellitus is a leading cause of death worldwide, with a total global prevalence exceeding 450 million individuals [1]. Diabetes is associated with a significantly elevated risk of cardiovascular death and hospitalisation for heart failure (HF) [4, 5]. There remains no specific treatment for HF or its development in individuals with diabetes. Despite extensive efforts to characterise diabetes-induced HF, inherent cellular mechanisms underpinning cardiac dysfunction in diabetes remain to be ascertained
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