Bone morphogenetic protein-4 induces upregulation of Cav3.1 Ca²⁺ channels in HL-1 atrial myocytes

Pflugers Arch. 2014 Nov;466(11):2049-57. doi: 10.1007/s00424-014-1459-5. Epub 2014 Feb 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / genetics*
  • Bone Morphogenetic Protein 4 / metabolism*
  • Calcium Channels, T-Type / genetics*
  • Calcium Channels, T-Type / metabolism*
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism
  • Cell Line, Tumor
  • Heart Atria / metabolism
  • Heart Failure / genetics
  • Heart Failure / metabolism
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism*
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • RNA, Messenger / genetics
  • Reactive Oxygen Species / metabolism
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Cacna1g protein, mouse
  • Calcium Channels, T-Type
  • RNA, Messenger
  • Reactive Oxygen Species
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases