Effects of mechanical stress and carvedilol in lamin A/C-deficient dilated cardiomyopathy.
BACKGROUND
Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking.


OBJECTIVE
Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna(+/-)) mice.


RESULTS
Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna(+/-) mice develop adult-onset DCM with relatively more severe disease in males. Lmna(+/-) cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna(+/-) mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna(+/-) mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna(+/-) mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna(+/-) mice from 12 to 40 weeks with the beta-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice.


CONCLUSIONS
These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts.
Chandar
Suchitra
S
Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool St, PO Box 699, Darlinghurst NSW 2010, Australia.
Yeo
Li Sze
LS
Leimena
Christiana
C
Tan
Ju-Chiat
JC
Xiao
Xiao-Hui
XH
Nikolova-Krstevski
Vesna
V
Yasuoka
Yoshinori
Y
Gardiner-Garden
Margaret
M
Wu
Jianxin
J
Kesteven
Scott
S
Karlsdotter
Lina
L
Natarajan
Shweta
S
Carlton
Arthur
A
Rainer
Stephen
S
Feneley
Michael P
MP
Fatkin
Diane
D
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic; D017209:Apoptosis; D002227:Carbazoles / Q000627:therapeutic use*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000077261:Carvedilol; D003250:Constriction; D003893:Desmin / Q000032:analysis; D005260:Female; D005838:Genotype; D006321:Heart / Q000503:physiopathology*; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D009997:Osmotic Pressure; D010805:Physical Conditioning, Animal; D011412:Propanolamines / Q000627:therapeutic use*; D013314:Stress, Mechanical; D018487:Ventricular Dysfunction, Left / Q000473:pathology / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D003893:Desmin; D034904:Lamin Type A; D011412:Propanolamines; C440308:lamin C; D000077261:Carvedilol