Cardiac FGFR1 levels were reduced by 45% in diabetic heart failure patients, and FGFR1 overexpression mitigated diabetes-induced cardiac dysfunction and vascular impairment.
Does cardiac FGFR1 signaling modulate cardiac and vascular dysfunction in diabetic heart failure?
Cardiac FGFR1 signaling protects against diabetic heart failure by mitigating cardiac dysfunction and promoting angiogenesis via the paracrine release of MFG-E8.
Absolute Event Rate: 0% vs 0%
Abstract Diabetes has been recognized as a growing global health concern for decades. One of the common and detrimental effects of prolonged diabetes is Diabetic heart failure (DHF). Existing literature recognizes multiple disrupted pathophysiological mechanisms as the consequence and a contributing factor of DHF. However, there is still a deficiency of robust treatment and prevention strategies for DHF. In this study, we investigated the role of fibroblast growth factor receptor 1 (FGFR1) mediated signalling cascade in the pathogenesis of DHF. This study utilised unbiased large-scale screenings like RNA sequencing and Mass spectrometry to validate disrupted cardiac FGFR1 signalling in DHF. Additionally, a cardiomyocyte-specific fgfr1 knockout mice model was generated and fed with a 45% high-fat-high-sucrose diet concomitant with 40mg/kg of streptozotocin injections to induce DHF. The AAV9 gene delivery system was used to generate cardiomyocyte-specific overexpression of FGFR1. The cardiac function was assessed using 2D echocardiography while multiple morphological staining techniques were used to determine cardiac hypertrophy, fibrosis, and cell death. In vitro co-culture experiments were conducted on induced pluripotent stem cells derived cardiomyocytes (iPSC-CMs) and human umbilical vein endothelial cells (HUVECs). We hypothesised that cardiac FGFR1 signalling plays an important pathogenic role in the development and progression of DHF. We demonstrated that FGFR1 levels were reduced by 45% in human DHF patients when compared to their corresponding controls. Additionally, our in vivo studies showed that FGFR1 deletion exacerbated diabetes-induced cardiac dysfunction as well as pathological remodelling. In contrast, these effects were mitigated with cardiac FGFR1 overexpression. Interestingly, we also discovered that impaired FGFR1 signalling in the cardiomyocytes aggravated angiogenic abnormalities in the endothelial cells of the diabetic heart, as evidenced by reduced capillary density, highlighting a novel and unexplored paracrine role of cardiac FGFR1 signalling in DHF. Mechanistically, our unbiased cytokine screening identified an angiogenic factor, milk fat globule epidermal growth factor 8 (MFG-E8) released from the cardiomyocytes with FGFR1 overexpression. The luciferase assay revealed that MFG-E8 release from the cardiomyocytes was transcriptionally regulated by CCAAT/enhancer binding protein beta (CEBPb). Our in vitro model confirmed the diminished secretion of MFG-E8 from the cardiomyocytes under palmitic acid-induced-diabetic stress that was enhanced by the overexpression of CEBPb. Overall, our study provides new undiscovered mechanistic insights into the paracrine actions of cardiac FGFR1 signalling on impaired angiogenesis in DHF. Therefore, targeting this signalling cascade can serve as a new therapeutic potential for treating both DHF-induced cardiac as well as vascular dysfunction.
Gare et al. (Sat,) relataram uma outra. Os níveis de FGFR1 cardíaco foram reduzidos em 45% em pacientes com insuficiência cardíaca diabética, e a superexpressão de FGFR1 mitigou a disfunção cardíaca induzida por diabetes e a lesão vascular.