TY - JOUR
T1 - Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction
AU - Unsoeld, Bernhard
AU - Kaul, Axel
AU - Sbroggi, Mauro
AU - Schubert, Carola
AU - Regitz-Zagrosek, Vera
AU - Brancaccio, Mara
AU - Damilano, Federico
AU - Hirsch, Emilio
AU - Van Bilsen, Marc
AU - Munts, Chantal
AU - Sipido, Karin
AU - Bito, Virginie
AU - Detre, Elke
AU - Wagner, Nana Maria
AU - Schaefer, Katrin
AU - Seidler, Tim
AU - Vogt, Johannes
AU - Neef, Stefan
AU - Bleckmann, Annalen
AU - Maier, Lars S.
AU - Balligand, Jean Luc
AU - Bouzin, Caroline
AU - Ventura-Clapier, Renee
AU - Garnier, Anne
AU - Eschenhagen, Thomas
AU - El-Armouche, Ali
AU - Knoell, Ralph
AU - Tarone, Guido
AU - Hasenfuss, Gerd
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach. Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusins overexpression strongly reduced mortality (43.2 in wild-type vs. 27.3 in melusin-TG, P 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility. Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.
AB - Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach. Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusins overexpression strongly reduced mortality (43.2 in wild-type vs. 27.3 in melusin-TG, P 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility. Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.
KW - Infarction
KW - Chaperon
KW - Map kinase
KW - Remodelling
KW - Transgenic animal models
U2 - 10.1093/cvr/cvt235
DO - 10.1093/cvr/cvt235
M3 - Article
C2 - 24130190
SN - 0008-6363
VL - 101
SP - 97
EP - 107
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -