Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction

TY - JOUR

T1 - Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction

AU - Unsöld, Bernhard

AU - Kaul, Axel

AU - Sbroggiò, 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 - Schäfer, 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, Renée

AU - Garnier, Anne

AU - Eschenhagen, Thomas

AU - El-Armouche, Ali

AU - Knöll, Ralph

AU - Tarone, Guido

AU - Hasenfuß, Gerd

PY - 2014/1/1

Y1 - 2014/1/1

N2 - AIMS: 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.METHODS AND RESULTS: 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 melusin's 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.CONCLUSIONS: 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 - AIMS: 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.METHODS AND RESULTS: 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 melusin's 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.CONCLUSIONS: 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.

U2 - 10.1093/cvr/cvt235

DO - 10.1093/cvr/cvt235

M3 - SCORING: Journal article

C2 - 24130190

VL - 101

SP - 97

EP - 107

JO - CARDIOVASC RES

JF - CARDIOVASC RES

SN - 0008-6363

IS - 1

ER -