Work

KLF15 Negatively Regulates Cardiac Fibrosis and SDF-1β Attenuates Cardiac Fibrosis Through KLF15 Pathway in Type 2 Diabetic Mice

Year: 2020

Type: preprint

Abstract: Background: Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. Cardiac fibrosis is the major pathologic changes, for which the effective and safe approaches remain not available. Methods: Wild-type mice and conditional knockout of cardiac specific Klf15 gene (Klf15-cKO) mice were fed with either high fat diet (HFD, 60% kcal from fat) or normal diet (ND, 10% kcal from fat) for 3 months and then injected with streptozotocin or vehicle. Five days later mice with hyperglycemia (3 h fasting blood glucose level ≥ 250 mg/dL) were defined as type 2 diabetes (T2D). All T2D and age-matched control mice that were continually received their HFD or ND for 6 months were treated with or without SDF-1β at 5 mg/kg body-weight twice a week for 3 months. At the end of 9-month study, after cardiac functions measured, mice were euthanized, for collecting heart tissue. For the in vitro study, H9C2 cells were exposed to palmitate to mimic in vivo condition of T2D.Results: SDF-1β treatment attenuated T2D-induced cardiac dysfunction and fibrosis and down-regulated KLF15 expression in wild type diabetic mice. The inhibitory effect of SDF-1β on cardiac fibrosis was abolished in Klf15-cKO/T2D mice, demonstrating the KLF15-dependence for this protection. Pre-treatment of H9C2 cells with the relevant siRNAs, followed by treatment with palmitate or SDF-1b or palmitate/SDF-1b demonstrated that SDF-1β inhibited palmitate-induced myocardial fibrosis through its receptor CXCR7 mediated activation of p38β MAPK and subsequent blockade of KLF15 down-regulation. Conclusions: T2D-promoted cardiac fibrosis and dysfunction were prevented with SDF-1β treatment by up-regulating KLF15 expression. Conditional knockout of cardiac specific Klf15 gene abolishes SDF-1β prevention of cardiac fibrosis but not cardiac dysfunction. The SDF-1β’s anti-fibrosis effect in the heart of T2D is probably mediated through CXCR7-mediated p38β MAPK activation of KLF15 function.

Source: Research Square

DOI: 10.21203/rs.3.rs-112222/v1