Abstract: SA-PO877

OPA1 Disruption Is Involved in the Development of Arterial Calcification in CKD

Session Information

  • Vascular Calcification
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Mineral Disease

  • 1205 Vascular Calcification

Authors

  • Guan, Fengying, College of Basic Medical Sciences, Jilin University, , Changchun, China
  • Chen, Li, College of Basic Medical Sciences, Jilin University, , Changchun, China
  • Li, Junnan, College of Basic Medical Sciences, Jilin University, , Changchun, China
  • Lim, Kenneth, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Feng, Linjing, College of Basic Medical Sciences, Jilin University, , Changchun, China
  • Zhao, Yali, College of Basic Medical Sciences, Jilin University, , Changchun, China
  • Teng, Fei, College of Basic Medical Sciences, Jilin University, , Changchun, China
  • Ho, Li-lun, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hiemstra, Thomas F., University of Cambridge, Cambridge, United Kingdom
  • Lu, Tzongshi, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Arterial calcification is a significant contributor to cardiovascular disease in patients with Chronic Kidney Disease (CKD). OPA1 is a GTPase of the dynamin family that functions in the mitochondrial inner membrane. It is involved in 1) maintenance of the respiratory chain and membrane potential; 2) cristae organization and control of apoptosis; and 3) stabilization of mitochondrial DNA. OPA1 protect cells from mitochondrial dysfunction by blocking intramitochondrial cytochrome c redistribution, which proceeds remodeling of the cristae in the presence of mitofusin 1 (MFN1). Our preliminary data has shown that OPA1 mediated disruption of mitochondrial dynamics may be involved in β-cell damage in type 2 diabetes. In this study, we investigated the role of OPA1 in human arteries from healthy and CKD patients.

Methods

Human arteries were collected from healthy (n=15) and CKD (n=15) patients. Arterial calcification was analyzed qualitatively by Alizarin Red. Total RNA from human arteries was extracted using the Nucleospin RNA isolation kit. cDNA was synthesized and fragmented using SMART-seq2 and Nextera XT (Illumina), respectively to generate libraries for sequencing on Hi-seq 2000 (Illumina). Five million single-ended raw reads from each sample were mapped to the human reference genome consortium GRCh38 by Burrows-Wheeler Aligner (BWA). Gene analysis were performed by the combinations of fold-changes on log 2 ratio, and p value < 0.05.

Results

Human arteries from CKD patients had extensive medial calcification while arteries from healthy controls did not develop significant calcification. RNA sequencing analysis revealed that OPA1 was significantly downregulated (Fold changes, FC, 2.33) in CKD arteries compared to arteries from healthy patients. CKD arteries had also reduced MFN1 (FC=1.83) and the downstream anti-apoptotic Bcl2 gene (FC=4.52). Both caspase 3 (FC=2.6) and cytochrome c (FC=2.29) expression were significantly increased in CKD arteries compared to control.

Conclusion

Mitochondrial OPA1 and MFN1 dysfunction may be involved in the pathogenesis of accelerated arterial calcification in CKD. Further investigation into the molecular mechanisms are needed.

Funding

  • Private Foundation Support