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Articles by S Rainer
Total Records ( 1 ) for S Rainer
  S Chandar , L. S Yeo , C Leimena , J. C Tan , X. H Xiao , V Nikolova Krstevski , Y Yasuoka , M Gardiner Garden , J Wu , S Kesteven , L Karlsdotter , S Natarajan , A Carlton , S Rainer , M. P Feneley and D. Fatkin

Rationale: 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.

Methods and 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 β-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.

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