title: Tetrandrine reverses human cardiac myofibroblast activation and myocardial fibrosis.
abstract: Tetrandrine (TTD) is a calcium channel blocker with documented antifibrotic actions. In this study, for the first time, we identified that TTD can directly prevent in vitro human cardiac myofibroblast activation and limit in vivo myocardial fibrosis. In vitro, cardiac myofibroblasts from human atrial biopsies (N = 10) were seeded in three-dimensional collagen matrices. Cell-collagen constructs were exposed to transforming growth factor-β1 (10 ng/ml), with or without TTD (1 and 5 μM) for 48 h. Collagen gel contraction, myofibroblast activation (α-smooth muscle actin expression), expression of profibrotic mRNAs, and rate of collagen protein synthesis were compared. TTD decreased collagen gel contraction (79.7 ± 1.3 vs 60.1 ± 8.9%, P < 0.01), α-smooth muscle actin expression (flow cytometry), collagen synthesis ([(3)H]proline incorporation), and collagen mRNA expression. Cell viability was similar between groups (annexin positive cells: 1.7 vs. 1.4%). TTD inhibited collagen gel contraction in the presence of T-type and L-type calcium channel blockers, and the intracellular calcium chelator BAPTA-AM (15 μM), suggesting that the observed effects are not mediated by calcium homeostasis. In vivo, Dahl salt-sensitive hypertensive rats were treated with variable doses of TTD (by intraperitoneal injection over 4 wk) and compared with untreated controls (N = 12). Systemic blood pressure was monitored by tail cuff. Myocardial fibrosis and left ventricular compliance were assessed by histology and passive pressure-volume analysis. Myocardial fibrosis was attenuated compared with untreated controls (%collagen area: 9.4 ± 7.3 vs 2.1 ± 1.0%, P < 0.01). Left ventricular compliance was preserved. In conclusion, TTD reverses human cardiac myofibroblast activation and myocardial fibrosis, independent of calcium channel blockade.
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Guoqi
authors: G
authors: Teng
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Daniyil
authors: D
authors: Svystonyuk
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Holly E M
authors: HE
authors: Mewhort
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Jeannine D
authors: JD
authors: Turnbull
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Darrell D
authors: DD
authors: Belke
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Henry J
authors: HJ
authors: Duff
authors: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada paul.fedak@gmail.com.
authors: Paul W M
authors: PW
authors: Fedak
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020517:Atrial Appendage / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D065096:Calcium Chelating Agents / Q000494:pharmacology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D005782:Gels; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020303:Rats, Inbred Dahl; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D065096:Calcium Chelating Agents; D005782:Gels; C009438:tetrandrine; D003094:Collagen; D002118:Calcium
keywords: diastolic dysfunction; extracellular matrix; fibroblast; fibrosis