title: Enhanced Ca²+ influx through cardiac L-type Ca²+ channels maintains the systolic Ca²+ transient in early cardiac atrophy induced by mechanical unloading.
abstract: Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca(2+) transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca(2+) transients, we investigated Ca(2+) cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca(2+) content was reduced by ~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca(2+) sparks and a diminished systolic Ca(2+) release, even though the expression of ryanodine receptors was increased by ~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca(2+) influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type Ca(2+) channels (LTCC) were upregulated in atrophic myocardium. These data suggest that in early cardiac atrophy induced by mechanical unloading, an augmented sarcolemmal Ca(2+) influx through LTCC fully compensates for a reduced systolic SR Ca(2+) release to preserve the Ca(2+) transient. This interplay involves an electrophysiological remodelling as well as changes in the expression of cardiac ion channels.
authors.affiliation: Department of Cellular and Integrative Physiology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20246, Hamburg, Germany, schwoerer@uke.de.
authors.forename: A P
authors.initials: AP
authors.lastname: Schwoerer
authors.forename: S
authors.initials: S
authors.lastname: Neef
authors.forename: I
authors.initials: I
authors.lastname: Broichhausen
authors.forename: J
authors.initials: J
authors.lastname: Jacubeit
authors.forename: M
authors.initials: M
authors.lastname: Tiburcy
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.forename: D
authors.initials: D
authors.lastname: Biermann
authors.forename: M
authors.initials: M
authors.lastname: Didié
authors.forename: C
authors.initials: C
authors.lastname: Vettel
authors.forename: L S
authors.initials: LS
authors.lastname: Maier
authors.forename: W H
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: L
authors.initials: L
authors.lastname: Carrier
authors.forename: T
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: T
authors.initials: T
authors.lastname: Volk
authors.forename: A
authors.initials: A
authors.lastname: El-Armouche
authors.forename: H
authors.initials: H
authors.lastname: Ehmke
mesh_terms: D000200:Action Potentials; D000818:Animals; D001284:Atrophy / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D016027:Heart Transplantation; D008297:Male; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016042:Transplantation, Heterotopic
chemical_list: D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium