Journal Article

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

Dhanani, Mehul, Patel, Hemal H., McKirnan, M. Dan, Ichikawa, Yasuhiro, Song, Young, Harrington, Elizabeth O., Leem, Joseph, Braza, Julie, Hammond, H. Kirk, Roth, David M.

2023

Overview

Role of blood-based factors in development and progression of heart failure (HF) is poorly characterized. Blood contains factors released during pathophysiological states that may impact cellular function and provide mechanistic insights to HF management. We tested effects of blood from two distinct HF models on cardiac metabolism and identified possible cellular targets of the effects. 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 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-blotting and electron microscopy were performed to evaluate mitochondrial proteins and morphology. Brief exposure to HF plasma decreased cardiac tissue respiration. Endothelial cell respiration was most impacted by exposure to HF plasma. Endothelial cell monolayer integrity was decreased by incubation with Dauno-HF plasma. Apoptosis and necrosis were increased in cells incubated with Dauno-HF plasma for 24 h. Down-regulation of voltage-dependent anion-selective channel (VDAC)-1, translocase of outer membrane 20 (Tom20), and mitochondrial fission factor (MFF) in cells exposed to Dauno-HF plasma and mitochondrial signal transducer and activator of transcription 3 (Stat3) and MFF in cells exposed to MI-HF plasma were observed. Mitochondrial structure was disrupted in cells exposed to HF plasma. These findings indicate that endothelial cells and mitochondrial structure and function may be 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine / Analysis / Animal tissues / Animals / Apoptosis / Bioenergetics / Biological markers / Biology and Life Sciences / Biomarkers / Blood / Blood plasma / Cell death / Cell metabolism / Cells / Complications and side effects / Congestive heart failure / Cytology / Daunorubicin / Electron microscopy / Endothelial cells / Endothelial Cells - metabolism / Endothelium / Energy Metabolism / Evaluation / Experiments / Exposure / Fatty acids / Health aspects / Heart Failure / Laboratory animals / Medicine and Health Sciences / Metabolism / Mice / Mitochondria / Mitochondria, Heart - metabolism / Myocardial infarction / Myocardium - metabolism / Necrosis / Ostomy / Pathophysiology / Phosphorylation / Physiology / Physiology, Pathological / Plasma / Prevention / Proteins / Rabbits / Research and Analysis Methods / Respiration / Respirometry / Risk factors / Sepsis / Stat3 protein / Structure-function relationships / Translocase