Impact of blood factors on endothelial cell metabolism and function in two diverse heart failure models

Abstract Background: Role of blood-based factors in development and progression of heart failure (HF) is poorly characterized. Blood contains myriads of factors released during pathophysiological states that may impact cellular function and provide mechanistic insights to HF management. In this study, we tested effects of blood from two distinct HF models on cardiac metabolism and identified possible cellular targets of the effects. Methods: Blood plasma was obtained from daunorubicin- and myocardial infarction-induced HF rabbits (Dauno-HF and MI-HF) and their controls (Dauno-Control and MI-Control). Effects of plasma on bioenergetics of myocardial tissue from healthy mice and cellular cardiac components; myoblasts, fibroblasts, macrophages, and endothelial cells were assessed using high-resolution respirometry and Seahorse flux analyzer. Since endothelial cell respiration was profoundly affected by HF plasma, effects of plasma on endothelial cell barrier function and death were further evaluated. Western-blot analysis and electron microscopic assessment were performed to detect alterations in mitochondrial proteins and morphology. Results: Brief exposure to HF plasma significantly decreased cardiac tissue respiration. Endothelial cell respiration was most impacted by exposure to HF plasma. Endothelial cell monolayer integrity was significantly decreased by incubation with Dauno-HF plasma. Apoptosis and necrosis were significantly increased in cells incubated with Dauno-HF plasma for 24 h. Significant down-regulation of VDAC-1, Tom20, and MFF in cells exposed to Dauno-HF plasma and mitochondrial Stat3 and MFF in cells exposed to MI-HF plasma were observed. Mitochondrial structure was disrupted in cells exposed to HF plasma.Conclusions: These findings indicate that endothelial cells and mitochondrial structure and function may be a primary target where HF pathology manifests and accelerates. High-throughput blood-based screening of HF may provide innovative ways to advance disease diagnosis and management.