title: Phytoestrogen, tanshinone IIA diminishes collagen deposition and stimulates new elastogenesis in cultures of human cardiac fibroblasts.
abstract: It has been previously reported that oral or intra-peritoneal administration of tanshinone IIA can alleviate the ventricular hypertrophy and fibrosis that develops in rats after experimental cardiac infarction. Our present studies, performed on cultures of human cardiac fibroblasts, investigated the mechanism by which tanshinone IIA produces these beneficial effects. We found that treatment of cardiac fibroblasts with 0.1-10µM tanshinone IIA significantly inhibited their deposition of collagen I, while enhancing production of new elastic fibers. Moreover, both anti-collagenogenic and pro-elastogenic effects of tanshinone IIA occurred only after selective activation of the G protein-coupled estrogen receptor (GPER). This subsequently leads to initiation of the PKA/CREB phosphorylation pathway that inversely modulated transcription of collagen I and elastin genes. Interestingly, treatment of human cardiac fibroblasts with tanshinone IIA additionally up-regulated the production of the 67-kDa elastin binding protein, which facilitates tropoelastin secretion, and increased synthesis of lysyl oxidase, catalyzing cross-linkings of tropoelastin. Moreover, tanshinone IIA also caused up-regulation in the synthesis of collagenolytic MMP-1, but down-regulated levels of elastolytic MMP-2 and MMP-9. In summary, our data validate a novel mechanism in which tanshinone IIA, interacting with a non-classic estrogen receptor, maintains the proper balance between the net deposition of collagen and elastin, allowing for optimal durability and resiliency of the newly deposited matrix.
authors: Physiology & Experimental Medicine Program, Heart Center, Hospital for Sick Children, 555 University Avenue, Ontario, Toronto, QJ;Canada M5G 1X8; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada; Second Clinical Medical College, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China; Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.
authors: Shuai
authors: S
authors: Mao
authors: Physiology & Experimental Medicine Program, Heart Center, Hospital for Sick Children, 555 University Avenue, Ontario, Toronto, QJ;Canada M5G 1X8.
authors: Yanting
authors: Y
authors: Wang
authors: Second Clinical Medical College, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China; Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.
authors: Minzhou
authors: M
authors: Zhang
authors: Physiology & Experimental Medicine Program, Heart Center, Hospital for Sick Children, 555 University Avenue, Ontario, Toronto, QJ;Canada M5G 1X8; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Electronic address: alek.hinek@sickkids.ca.
authors: Aleksander
authors: A
authors: Hinek
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D004547:Elastic Tissue / Q000378:metabolism*; D004549:Elastin / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D048789:Phytoestrogens / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014333:Tropoelastin / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D045784:Abietanes; D000894:Anti-Inflammatory Agents, Non-Steroidal; C115163:CREB1 protein, human; D024042:Collagen Type I; D017362:Cyclic AMP Response Element-Binding Protein; C109584:GPER1 protein, human; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D014333:Tropoelastin; C021751:tanshinone; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase; D017868:Cyclic AMP-Dependent Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Collagen; Elastin; Estrogen receptors; Human cardiac fibroblasts; Tanshinone IIA