GIST Professor Woo Jin Park leads an

international research team to reverse cardiac fibrosis

Fibrosis is a medical condition where excessive connective tissues form in organs, and this process occurs naturally in certain organs—such as the kidneys, liver, and lungs—as people become older. Cardiac fibrosis is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure, and heart failure is the most common cause of hospitalization in people over the age of 65. So finding an effective treatment for cardiac fibrosis is an important goal, especially as the world"s aging population continues to live longer.

Professor Woo Jin Park of the School of Life Sciences at the Gwangju Institute of Science and Technology (GIST) has led an international research team comprised of members from the Cardiovascular Research Center of the Icahn School of Medicine in New York, Benioff Children"s Hospital of the University of California in San Francisco, and Paean Biotechnology of the Chungnam National University in Daejeon, Korea.

CCN5 is one of six members of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family, and this family of proteins has been shown to play important roles in many processes, including proliferation, migration, adhesion, extracellular matrix regulation, angiogenesis, tumorigenesis, fibrosis, and implantation.

This research team examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload. This study was performed by obtaining human hearts from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined.

The study revealed that xpression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule.

This study concluded that CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.

The results of the study were published on April 5, 2016, in the online edition of the Journal of the American College of Cardiology in a paper entitled "Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis" and authored by Dongtak Jeong, Min-Ah Lee, Yan Li, Dong Kwon Yang, Changwon Kho, Jae Gyun Oh, Gyeongdeok Hong, Ahyoung Lee, Min Ho Song, Thomas J. LaRocca, Jiqiu Chen, Lifan Liang, Shinichi Mitsuyama, Valentina D"Escamard, Jason C. Kovacic, Tae Hwan Kwak, Roger J. Hajjar, and Woo Jin Park.

Professor Woo Jin Park said, "Fibrosis is known to cause diseases in various organs in addition to the heart, such as the kidney, livers, and lungs. This study showed that it is possible to reverse cardiac fibrosis, and we expect these results to contribute significantly to fibrosis research and treatment options."