Abstract: SA-PO990
Cytoskeletal Dysregulation in Uremic Cardiomyopathy
Session Information
- Hypertension and CVD: Mechanisms - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Lim, Kenneth, Massachusetts General Hospital, 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
- Siedlecki, Andrew M., Brigham and Women's Hospital, Harvard Medical School, 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
Ventricular remodeling involving left ventricular (LV) hypertrophy, dilatation and fibrosis in uremic cardiomyopathy contribute to the high rate of premature cardiovascular death in chronic kidney disease (CKD). Alterations in the cytoskeleton are well described in hypertrophied and failing myocardium and appear to be an important regulator of pro-fibrotic pathways in CKD. The mechanisms of cytoskeletal dysregulation in uremic cardiomyopathy remain largely unknown. Herein, we performed a comprehensive investigation of cytoskeletal adaptations in uremic cardiomyopathy.
Methods
We conducted a cross-sectional analysis of explanted human LV tissues from advanced CKD donors (n=23; hemodialysis (HD; n=20); peritoneal dialysis (PD; n=3)) compared to CAD (coronary artery disease; n=11) and healthy (n=20) controls. Primary human cardiomyocytes and cardiac-myofibroblasts were treated with calcification medium (CM) in time-course experiments (0-48 hours), in vitro. We developed a novel digital cell sorting study model using deconvolution to accurately assess hetereogenous transcriptomic profiles inherent of mixed-cell type tissues from RNA sequencing. qPCR and western blotting was used to confirm expression of target genes.
Results
Cross-sectional analysis revealed that the major cytoskeletal proteins β-tubulin and type III intermediate filament Vimentin, were significantly down-regulated in both CAD and CKD hearts compared to controls (p<0.01). However, major anchor protein Vinculin was upregulated in both CAD and CKD hearts compared to controls (p<0.05). Interestingly, β-actin, a critical component of the microfilament system was down-regulated in CAD hearts, but further down-regulated in CKD hearts compared to CAD and controls (p<0.01). Furthermore, on subanalysis HD patients had significantly lower β-actin expression compared to PD patients (p<0.01). Analysis of primary human cardiomyocytes and cardiac-myofibroblasts treated with CM revealed the same pattern of changes, in vitro.
Conclusion
We show for the first time severely reduced β-actin expression in human CKD hearts compared to CAD and controls. These findings may contribute to accelerated cardiac remodeling in uremic conditions and may be affected by dialysis modality. Upregulation of Vinculin may be involved in reduced contractile function of cardiomyocytes in uremia.
Funding
- Private Foundation Support