Association of hypoxia and mitochondrial damage associated molecular patterns in the pathogenesis of vein graft failure: a pilot study

Coronary artery bypass grafting (CABG) is the standard treatment modality in revascularization of the myocardium. However, the graft failure remains the major complication following CABG procedure. Involvement of mitochondrial damage-associated molecular patterns (mt-DAMPs) in the pathogenesis of ve...

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Published in:	Translational research : the journal of laboratory and clinical medicine Vol. 229; pp. 38 - 52
Main Authors:	Thankam, Finosh G, Ayoub, Joseph G, Ahmed, Mohamed M Radwan, Siddique, Aleem, Sanchez, Thomas C, Peralta, Rafael A, Pennington, Thomas J, Agrawal, Devendra K
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-03-2021
Subjects:	Animals Cell Hypoxia Coronary Artery Bypass - adverse effects Coronary Artery Bypass - methods Coronary artery bypass grafting Damage associated molecular patterns Disease Models, Animal Female Graft failure Hypoxia Hypoxia - physiopathology Mitochondria Mitochondria - metabolism Mitochondria - pathology Mitochondrial dysfunction Mitochondrial Membranes - pathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Pilot Projects Proteins - metabolism Swine Swine, Miniature Treatment Failure Veins - pathology Veins - surgery Veins - transplantation Venous Thrombosis Hypoxia Mitochondria Mitochondrial dysfunction Damage associated molecular patterns Coronary artery bypass grafting Graft failure
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Summary:	Coronary artery bypass grafting (CABG) is the standard treatment modality in revascularization of the myocardium. However, the graft failure remains the major complication following CABG procedure. Involvement of mitochondrial damage-associated molecular patterns (mt-DAMPs) in the pathogenesis of vein-graft failure is largely unknown. Here, we investigated the expression of major protein-mt-DAMPs, cytochrome-C (Cyt-C), heat shock protein-60 (Hsp-60), mitochondrial transcription factor A (mtTFA), in the occluded graft and associated tissues, including distal left anterior descending (LAD), LAD adjacent to anastomosis, and left internal mammary artery (LIMA) in the microswine CABG model. The protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was significantly decreased in the graft and LIMA, whereas the protein expression of hypoxia inducible factor-1 alpha (HIF-1α) and Cyt-C was decreased and that of mtTFA and Hsp60 was increased in all tissues compared to controls. There was no significant difference in the protein expression of citrate synthase, complex-1, and mitochondrial pyruvate dehydrogenase in the graft and associated tissues compared to control. Hypoxia in cultured smooth muscle cells (SMCs) significantly upregulated all mitochondrial biomarkers and mt-DAMPs compared to normoxia. The increased reactive oxygen species (ROS) content and compromised membrane integrity in the hypoxic SMCs correlated well with increased mt-DAMPs in the graft and associated tissues, suggesting a possible role of mt-DAMPs in the pathogenesis of graft failure. These findings suggest that the pathological signals elicited by mt-DAMPs could reveal targets for better therapeutic approaches and diagnostic strategies in the management of CABG graft failure.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1931-5244 1878-1810
DOI:	10.1016/j.trsl.2020.08.010