Abstract
AimsHomozygosity for a four‐missense single‐nucleotide polymorphism haplotype of the human BPIFB4 gene is enriched in long‐living individuals. Delivery of this longevity‐associated variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell‐derived factor‐1 (SDF‐1). Here, we investigated if delivery of the LAV‐BPIFB4 gene may attenuate the progression of diabetic cardiomyopathy.Methods and resultsCompared with age‐matched lean controls, diabetic db/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV‐BPIFB4 gene therapy using an adeno‐associated viral vector serotype 9 (AAV9). In contrast, AAV9 wild‐type‐BPIFB4 exerted no benefit. Interestingly, LAV‐BPIFB4‐treated mice showed increased SDF‐1 levels in peripheral blood and myocardium and up‐regulation of the cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF‐1 up‐regulation was instrumental to LAV‐BPIFB4‐induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF‐1 CXCR4 receptor.ConclusionsIn mice with type‐2 diabetes, LAV‐BPIFB4 gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes‐induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.
Highlights
Diabetic cardiomyopathy has a complex pathogenic basis and is difficult to treat by targeting a single candidate mechanism.[1,2] The genetics of healthy longevity may inspire novel treatments for this condition
In mice with type-2 diabetes, Longevity-associated variant (LAV)-bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes-induced stress
The present study investigates the potential of LAV-BPIFB4 gene therapy and participation of stromal cell-derived factor-1 (SDF-1)/CXCR4 axis in halting the progression of diabetic cardiomyopathy
Summary
Diabetic cardiomyopathy has a complex pathogenic basis and is difficult to treat by targeting a single candidate mechanism.[1,2] The genetics of healthy longevity may inspire novel treatments for this condition. Long-living individuals are protected from the consequences of age-related pathologies. Their offspring show a lower incidence of cardiovascular disease, suggesting the healthy phenotype can be transmitted vertically through generations.[3] We postulate that horizontal transfer of genes associated with healthy longevity may be a novel way to fight cardiovascular complications in people with diabetes. The prevalence of LAV homozygosity is 14% in centenarians and 10% in controls.[6]
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