TY - JOUR
T1 - Association of hypoxia and mitochondrial damage associated molecular patterns in the pathogenesis of vein graft failure
T2 - a pilot study
AU - Thankam, Finosh G.
AU - Ayoub, Joseph G.
AU - Ahmed, Mohamed M.Radwan
AU - Siddique, Aleem
AU - Sanchez, Thomas C.
AU - Peralta, Rafael A.
AU - Pennington, Thomas J.
AU - Agrawal, Devendra K.
N1 - Funding Information:
Funding: The research work of DK Agrawal is supported by research grants R01HL128063 , R01HL144125 , and R01HL147662 from the National Institutes of Health, USA . The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Coronary artery bypass grafting
KW - Damage associated molecular patterns
KW - Graft failure
KW - Hypoxia
KW - Mitochondria
KW - Mitochondrial dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85091245678&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091245678&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2020.08.010
DO - 10.1016/j.trsl.2020.08.010
M3 - Article
C2 - 32861831
AN - SCOPUS:85091245678
JO - Translational Research
JF - Translational Research
SN - 1931-5244
ER -