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Abstract: PO1836

Focal Adhesion Kinase: A Major Regulator of Myocardial Failure in CKD

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Halim, Arvin, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Narayanan, Gayatri, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hato, Takashi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Lu, Tzongshi, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Lim, Kenneth, Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

The focal adhesion pathway is essential in signal communication between the extracellular matrix and the cytoskeleton. Failure of this signaling pathway results in cytoskeletal dysfunction and has been shown to be intricately involved in the progression of ischemic cardiomyopathy. Whether this occurs in CKD-associated cardiomyopathy is currently unknown. In this study, our aim was to investigate the role of focal adhesion kinase (FAK), a central component of the focal adhesion pathway in the failing heart in CKD.

Methods

We performed a cross-sectional cohort study of explanted human heart tissues from hemodialysis-dependent (HD, n=19), hypertension with preserved renal function (HTN, n=10), and healthy control (n=21) donors. Left ventricular (LV) tissues were subjected to RNA sequencing, qPCR, and protein analyses. Mechanistic and interference RNA studies using in vitro human ventricular cardiac fibroblast models were also conducted.

Results

Hearts from HD donor exhibited significant myocardial fibrosis (p<0.01) compared to HTN and control. HD and HTN hearts had higher heart weights (p<0.01) and greater LV wall thickness (p<0.01) compared to control hearts. RNA-sequencing revealed that the focal adhesion pathway was one of the most perturbed pathways in HD hearts compared to control. FAK mRNA and protein expression was significantly upregulated (p<0.05), and major cytoskeletal proteins associated with the focal adhesion pathway, including β-actin (p<0.01), β-tubulin (p<0.01), vinculin (p<0.05), and vimentin (p<0.01) were significantly dysregulated in HD hearts compared to control. Uremic mineral stressors (high phosphate and high calcium) decreased FAK expression as well as β-tubulin (p<0.05) and vimentin, and promoted cleavage of FAK and vimentin, in vitro. Concurrent FAK siRNA transfection and mineral stress significantly decreased both full-length and cleaved FAK expression (p<0.05) and further dysregulated vimentin (p<0.05) and vinculin (p<0.05) expression, in vitro.

Conclusion

FAK and the focal adhesion pathway plays a central role in the development of CKD-associated cardiomyopathy and appears to preserve the dynamic formation of the cytoskeleton in HD hearts. These findings suggest a potential therapeutic role for targeting the focal adhesion pathway in the management of cardiac remodeling in CKD.