RESUMO
Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.
RESUMO
The prevalence of diabetes has reached epidemic proportions and is placing a significant burden on healthcare systems globally. Diabetes has a detrimental impact on many organs in the human body, including accelerating the development of micro- and macrovascular complications. Current therapeutic options to treat diabetic complications have their limitations. Importantly, many slow but fail to reverse the progression of diabetic complications. Bone morphogenetic proteins (BMPs) are a highly conserved subgroup of the transforming growth factor ß (TGFß) superfamily, signaling via serine/threonine kinase receptors, that have recently been implicated in glucose homeostasis and insulin resistance in the setting of diabetes. Downstream of the receptors, the signal can be transduced via the canonical Smad-dependent pathway or the noncanonical Smad-independent pathways. BMPs are essential in organ development, tissue homeostasis, and, as expected, disease pathogenesis. In fact, deletion of BMPs can be embryonically lethal or result in severe organ abnormalities. This review outlines the BMP signaling pathway and its relevance to diabetic complications, namely, diabetic nephropathy, diabetes-associated cardiovascular diseases, and diabetic retinopathy. Understanding the complexities of BMP signaling and particularly its tissue-, cellular-, and time-dependent actions will help delineate the underlying pathogenesis of the disease and may ultimately be harnessed in the treatment of diabetes-induced complications. This would replicate progress made in numerous other diseases, including cancer and atherosclerosis.
