期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 308, 期 12, 页码 H1564-H1574出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00126.2015
关键词
fibrosis; fibroblast; extracellular matrix; diastolic dysfunction
资金
- Heart and Stroke Foundation of Alberta, NWT, and Nunavut
- AIHS
- Alberta Innovates [201201075, 201500229] Funding Source: researchfish
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-beta 1 (10 ng/ml), with or without TTD (1 and 5 mu M) for 48 h. Collagen gel contraction, myofibroblast activation (alpha-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), alpha-smooth muscle actin expression (flow cytometry), collagen synthesis ([H-3]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 mu M), 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.
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