Andrews Rachel M, Naik Saumya, Pelletier Katie, Jacobs J Roger
Department of Biology, McMaster University, Hamilton, Canada.
Department of Zoology, University of British Columbia, Vancouver, Canada.
PLoS One. 2025 Aug 22;20(8):e0330487. doi: 10.1371/journal.pone.0330487. eCollection 2025.
Cardiovascular disease is characterized by aberrant and excessive extracellular matrix (ECM) remodelling, termed fibrosis. Fibrotic remodelling is typically triggered by inflammation, which occurs systemically in obesity. Despite the contribution of fibrosis to adverse clinical outcomes and disease progression, there are no available treatments for this condition. Developing therapeutics for chronic conditions requires an understanding of in vivo ECM regulation, and how the ECM responds to a systemic challenge. We have therefore developed a Drosophila model for obesity via chronic high fat diet feeding of larvae and evaluated the response of the cardiac ECM to this metabolic challenge. We found that this model displays a striking reorganisation of the cardiac ECM, with fibres oriented anterior to posterior, rather than in a complex network, suggesting tension modulation is altered. We also observe corresponding deficits in heart function, with high fat diet treatments resulting in an inability to contract the heart effectively at systole. Our study reveals that different genotypes tolerate different levels of dietary fat, and that some genotypes may require a different dietary supplementation regime to generate a cardiac phenotype. In summary, the Drosophila model for chronic high fat diet recapitulates many of the defects observed in human cardiovascular disease, allowing further evaluation of genetic and environmental influences on cardiac structure and physiology in disease states.
心血管疾病的特征是细胞外基质（ECM）发生异常且过度的重塑，即纤维化。纤维化重塑通常由炎症引发，而炎症在肥胖症中是全身性发生的。尽管纤维化会导致不良临床后果和疾病进展，但目前尚无针对这种情况的有效治疗方法。开发针对慢性病的疗法需要了解体内ECM的调节机制，以及ECM如何应对全身性挑战。因此，我们通过对幼虫进行慢性高脂饮食喂养建立了果蝇肥胖模型，并评估了心脏ECM对这种代谢挑战的反应。我们发现，该模型显示出心脏ECM的显著重组，纤维从前向后排列，而非形成复杂网络，这表明张力调节发生了改变。我们还观察到心脏功能存在相应缺陷，高脂饮食处理导致心脏在收缩期无法有效收缩。我们的研究表明，不同基因型对不同水平的膳食脂肪耐受性不同，并且某些基因型可能需要不同的膳食补充方案才能产生心脏表型。总之，慢性高脂饮食果蝇模型概括了人类心血管疾病中观察到的许多缺陷，从而能够进一步评估疾病状态下遗传和环境对心脏结构和生理的影响。
