Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin

Authors

Farhan Rizvi, Advocate Aurora HealthFollow
Alessandra DeFranco, Advocate Aurora HealthFollow
Ramail Siddiqui, Advocate Aurora HealthFollow
Ulugbek Negmadjanov, Advocate Aurora HealthFollow
Larisa Emelyanova, Advocate Aurora HealthFollow
Alisher Holmuhamedov, Advocate Aurora Health
Gracious R. Ross, Advocate Aurora HealthFollow
Yang Shi, Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Advocate Aurora HealthFollow
Ekhson Holmuhamedov, Advocate Aurora HealthFollow
David C. Kress, Advocate Aurora HealthFollow
A. Jamil Tajik, Aurora Cardiovascular Services, Advocate Aurora Health; University of Wisconsin School of Medicine and Public HealthFollow
Arshad Jahangir, Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora UW Medical GroupFollow

Recommended Citation

Rizvi F, Defranco A, Siddiqui R, et al. Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin. American Journal of Physiology, Cell Physiology. 2016;311(2):C330-9.

Affiliations

Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Cardiovascular Services

Abstract

Fibroblasts, the most abundant cells in the heart, contribute to cardiac fibrosis, the substrate for the development of arrythmogenesis, and therefore are potential targets for preventing arrhythmic cardiac remodeling. A chamber-specific difference in the responsiveness of fibroblasts from the atria and ventricles toward cytokine and growth factors has been described in animal models, but it is unclear whether similar differences exist in human cardiac fibroblasts (HCFs) and whether drugs affect their proliferation differentially. Using cardiac fibroblasts from humans, differences between atrial and ventricular fibroblasts in serum-induced proliferation, DNA synthesis, cell cycle progression, cyclin gene expression, and their inhibition by simvastatin were determined. The serum-induced proliferation rate of human atrial fibroblasts was more than threefold greater than ventricular fibroblasts with faster DNA synthesis and higher mRNA levels of cyclin genes. Simvastatin predominantly decreased the rate of proliferation of atrial fibroblasts, with inhibition of cell cycle progression and an increase in the G0/G1 phase in atrial fibroblasts with a higher sensitivity toward inhibition compared with ventricular fibroblasts. The DNA synthesis and mRNA levels of cyclin A, D, and E were significantly reduced by simvastatin in atrial but not in ventricular fibroblasts. The inhibitory effect of simvastatin on atrial fibroblasts was abrogated by mevalonic acid (500 μM) that bypasses 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition. Chamber-specific differences exist in the human heart because atrial fibroblasts have a higher proliferative capacity and are more sensitive to simvastatin-mediated inhibition through HMG-CoA reductase pathway. This mechanism may be useful in selectively preventing excessive atrial fibrosis without inhibiting adaptive ventricular remodeling during cardiac injury.

Document Type

Article

PubMed ID

27335167