Abstract: SA-PO846
Transcriptomic Profiling of Mitochondrial Dysfunction in Uremic Cardiomyopathy
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Lim, Kenneth, Massachusetts General Hospital, Boston, Massachusetts, United States
- Xu, Frank, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Halim, Arvin, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Ho, Li-lun, Massachusetts Institute of Technology , Cambridge, Massachusetts, United States
- Kalim, Sahir, Massachusetts General Hospital/ Harvard Medical School, Cambridge, Massachusetts, United States
- Ankers, Elizabeth D., Massachusetts General Hospital, Boston, Massachusetts, United States
- Hiemstra, Thomas F., University of Cambridge, Cambridge, United Kingdom
- Thadhani, Ravi I., Cedars-Sinai, Los Angeles, California, United States
- Lu, Tzongshi, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background
Uremic cardiomyopathy is a life-limiting condition that occurs in chronic kidney disease (CKD). Emerging evidence suggests that mitochondrial dysfunction may be a cardinal event that occurs in the failing myocardium under uremic conditions. We previously reported mitochondrial structural deformity and reduction in its respiratory chain enzyme activity in septic rat hearts. These changes were mitigated by upregulation of the inducible molecular chaperone, Heat Shock Protein (HSP) 70. Whether HSP70 may induce cytoprotective effects in uremic cardiomyopathy is currently unknown. The goal of this study was to investigate mitochondrial changes and their association with the HSP70 system in uremic cardiomyopathy.
Methods
Human left ventricular tissues collected from CKD (n=23), CAD (n=11) and healthy donors (n=20) were subjected to RNA sequencing, ex vivo. We developed a digital cell sorting study model using deconvolution to enhance interpretation of heterogenous transcriptomic profiles inherent of mixed-cell type tissue. Primary human cardiomyocytes and cardiac-myofibroblasts were treated with calcification medium (CM) in time-course experiments (0-48 hours), in vitro.
Results
Cytoprotective mtHSP (HSPA9) and the HSP70 co-chaperone, Bcl2 associated Athanogene 1 (BAG1) were highly expressed in healthy control hearts compared to CKD and CAD. However, mitochondrial fusion regulation genes MFN1 and OPA1 were down-regulated in CKD hearts, together with down-regulation of downstream anti-apoptotic gene Bcl2 and up-regulation of pro-apoptotic genes cytochrome c, caspase 3, BAX and P53. The same pattern of changes were observed in cardiomyocytes and cardio-myofibroblasts treated with CM, in vitro. BAG1 was significantly increased at 6 hours prior to upregulation of Bcl2 at 12 hours after treatment. Furthermore, stress respondent genes, HSPA5 and DNAJB6 (HSP40) was significantly increased at 12 hours and 24 hours respectively in CM-treated primary cells.
Conclusion
The present study is the first to describe complex differential genomic changes involved in uremic cardiomyopathy. Mitochondrial dysfunction was associated with upregulation of apoptotic genes and reduced expression of cytoprotective HSP70 components. We postulate that induction of the HSP70 system may be a therapeutic target in uremic cardiomyopathy.
Funding
- Private Foundation Support