Cytoskeleton mediates negative inotropism and lusitropism of chromogranin A-derived peptides (human vasostatin1-78 and rat CgA₁₋₆₄) in the rat heart.
Cytoskeleton scaffold in cardiac myocytes provides structural support and compartmentalization of intracellular components. It is implicated in cardiac pathologies including hypertrophy and failure, playing a key role in the determinism of contractile and diastolic dysfunctions. Chromogranin A (CgA) and its derived peptides have revealed themselves as novel cardiovascular modulators. In humans, normal CgA levels considerably increase in several pathologies, including heart failure. Recent data have shown on the unstimulated rat heart that human recombinant Vasostatin-1 (hrVS-1) and rat chromogranin A 1-64 (rCgA₁₋₆₄) induce negative inotropic and lusitropic effects counteracting the β-adrenergic-dependent positive inotropism with a functional non-competitive antagonism. This study investigates, on the isolated Langendorff perfused rat heart, whether cardiac cytoskeleton is involved in the modulation of contractility and relaxation exerted by hrVS-1 and rCgA₁₋₆₄. Cytoskeleton impairment by either cytochalasin-D (actin polymerization inhibitor), BDM (myosin ATP-ase antagonist) or wortmannin (inhibitor of PI3-K/Akt transduction cascade), or W-7 (calcium-calmodulin antagonist) abolished hrVS-1 and rCgA₁₋₆₄-mediated inotropism and lusitropism. Using fluorescent phalloidin, we showed on rat cardiac H9C2 cells that hrVS-1 (10 nM÷10 µM) stimulates actin polymerization. Taken together these data indicate that in the rat heart, the actin cytoskeletal network strongly contributes to the cardiotropic action of CgA-derived peptides.
Angelone
Tommaso
T
Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy. t.angelone@unical.it
Quintieri
Anna Maria
AM
Goumon
Yannich
Y
Di Felice
Valentina
V
Filice
Elisabetta
E
Gattuso
Alfonsina
A
Mazza
Rosa
R
Corti
Angelo
A
Tota
Bruno
B
Metz-Boutigue
Marie-Hélène
MH
Cerra
Maria Carmela
MC
D000818:Animals; D002460:Cell Line; D053379:Chromogranin A / Q000494:pharmacology*; D003599:Cytoskeleton / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D053379:Chromogranin A; C506153:chromogranin A, rat