title: Bone morphogenetic protein-4 induces upregulation of Cav3.1 Ca²⁺ channels in HL-1 atrial myocytes.
abstract: Cardiac T-type Ca(2+) channels are reexpressed in atrial and ventricular myocytes under various pathological conditions such as post-myocardial infarction, hypertrophy, and heart failure, but relatively little is known about the mechanisms. Our previous study found that bone morphogenetic protein-4 (BMP4) was reexpressed in pathological cardiac hypertrophy models and BMP4-mediated cardiomyocyte hypertrophy. We hypothesized that BMP4 could upregulate cardiac T-type Ca(2+) channels in HL-1 atrial myocytes. The T-type Ca(2+) currents were recorded by using the patch-clamp technique, and the expressions of Cav3.1 and Cav3.2 were measured by real-time PCR method in HL-1 cells. BMP4 and Cav3.1 mRNA expressions increased in the left atrium from the pressure overload-induced hypertrophy of mice hearts. BMP4 treatment for 48 h induced increase of Cav3.1 but not Cav3.2 mRNA expression in HL-1 cells, and the increase was inhibited by BMP4 inhibitor noggin. Acute treatment with BMP4 did not affect T-type Ca(2+) currents, but chronic treatment (48 h) significantly increased the amplitude of T-type Ca(2+) currents in HL-1 cells. Chronic treatment with BMP4 induced upregulation of NADPH oxidase-4 (NOX4), increase of reactive oxygen species (ROS) level, and activation of mitogen-activated protein kinase (MAPK)-activated protein kinases c-jun N-terminal kinases (JNK) and p38. BMP4-induced upregulation of Cav3.1 mRNA was inhibited by NADPH oxidase inhibitor apocynin, the radical scavenger tempol, JNK inhibitor SP600125, and p38 inhibitor SB203580. In conclusion, BMP4 induces upregulation of Cav3.1 Ca(2+) channels and T-type Ca(2+) currents in HL-1 atrial myocytes through ROS/MAPK pathways.
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Baojian Road 157, Harbin, 150086, Heilongjiang Province, People's Republic of China.
authors: Chao-Wei
authors: CW
authors: Hu
authors: Qi
authors: Q
authors: Li
authors: Ying
authors: Y
authors: Zhang
authors: Yu-Hong
authors: YH
authors: Li
authors: Hong-Chao
authors: HC
authors: Jiang
authors: Ming-Yu
authors: MY
authors: Liu
authors: Shan-Liang
authors: SL
authors: Li
authors: Wei
authors: W
authors: Han
authors: De-Li
authors: DL
authors: Dong
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006325:Heart Atria / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C498197:Cacna1g protein, mouse; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases