title: Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin.
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.
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Farhan
authors.initials: F
authors.lastname: Rizvi
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Alessandra
authors.initials: A
authors.lastname: DeFranco
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Ramail
authors.initials: R
authors.lastname: Siddiqui
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Ulugbek
authors.initials: U
authors.lastname: Negmadjanov
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Larisa
authors.initials: L
authors.lastname: Emelyanova
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Alisher
authors.initials: A
authors.lastname: Holmuhamedov
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Gracious
authors.initials: G
authors.lastname: Ross
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and.
authors.forename: Ekhson
authors.initials: E
authors.lastname: Holmuhamedov
authors.affiliation: Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin.
authors.forename: David
authors.initials: D
authors.lastname: Kress
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin.
authors.forename: A Jamil
authors.initials: AJ
authors.lastname: Tajik
authors.affiliation: Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin; and Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin publishing44@aurora.org.
authors.forename: Arshad
authors.initials: A
authors.lastname: Jahangir
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000214:Acyl Coenzyme A; D016213:Cyclins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D019821:Simvastatin; D008798:Mevalonic Acid
keywords: atrium; heart disease; remodeling; statins; ventricles