title: A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling.
abstract: OBJECTIVE
  Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca(2+) signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) cycling and neurohumoral stimulation leading to hypertrophy is unknown.
  
  
  RESULTS
  In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca(2+) concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca(2+)-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure.
  
  
  CONCLUSIONS
  The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca(2+) cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.
authors.affiliation: Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
authors.forename: Juan E
authors.initials: JE
authors.lastname: Camacho Londoño
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Hammer
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Schröder
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Camacho Londoño
authors.affiliation: Innere Medizin III Universität des Saarlandes, 66421 Homburg, Germany.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Reil
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany Research Unit Cardiac Epigenetics, Department of Cardiology, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Oberhofer
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mannebach
authors.affiliation: Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Mathar
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Philipp
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Tabellion
authors.affiliation: Institut für Physiologie, Universität Regensburg, 93053 Regensburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, LMU, 80336 München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaestner
authors.affiliation: Innere Medizin III Universität des Saarlandes, 66421 Homburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.affiliation: Transmembrane Signaling Group, NIEHS, PO Box 12233, NC 27709, USA.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.affiliation: Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany marc.freichel@pharma.uni-heidelberg.de peter.lipp@uniklinikum-saarland.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.affiliation: Institut für Molekulare Zellbiologie, 66421 Homburg, Germany marc.freichel@pharma.uni-heidelberg.de peter.lipp@uniklinikum-saarland.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: D015220:Calcium Channels; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C096351:transient receptor potential cation channel, subfamily C, member 1; D000808:Angiotensinogen; D000804:Angiotensin II; D002118:Calcium
keywords: Background Ca2+ entry; Calcium; Cardiac remodelling; Ion channels; TRPC1/TRPC4