Published online before print October 8, 2009, doi: 10.1161/CIRCRESAHA.109.200303
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Submitted on December 8, 2008
Revised on September 17, 2009
Accepted on September 24, 2009
Conditional Ablation of Nonmuscle Myosin II-B Delineates Heart Defects in Adult Mice
Xuefei Ma ;
From the Laboratory of Molecular Cardiology (X.M., K.T., A.S., A.B., R.S.A., Q.W.), Pathology Core Facility (Z.-X.Y.), and Transgenic Mouse Core Facility (C.L.), National Heart, Lung, and Blood Institute; and Division of Veterinary Resources (P.Z.), NIH, Bethesda, Md; Cincinnati Children's Hospital Medical Center (J.A.T.), Ohio; and National Heart and Lung Institute (M.D.S.), Imperial College, London, United Kingdom.
* To whom correspondence should be addressed. E-mail: adelster{at}mail.nih.gov.
Rationale: Germline ablation of the cytoskeletal protein nonmuscle myosin (NM)II-B results in embryonic lethality, with defects in both the brain and heart. Tissue-specific ablation of NMII-B by a Cre recombinase strategy should prevent embryonic lethality and permit study of the function of NMII-B in adult hearts.
Objective: We sought to understand the function of NMII-B in adult mouse hearts and to see whether the brain defects found in germline-ablated mice influence cardiac development.
Methods and Results: We used a loxP/Cre recombinase strategy to specifically ablate NMII-B in the brains or hearts of mice. Mice ablated for NMII-B in neural tissues die between postnatal day 12 and 22 without showing cardiac defects. Mice deficient in NMII-B only in cardiac myocytes (B
MHC/BMHC mice) do not show brain defects. However, BMHC/BMHC mice display novel cardiac defects not seen in NMII-B germline-ablated mice. Most of the BMHC/BMHC mice are born with enlarged cardiac myocytes, some of which are multinucleated, reflecting a defect in cytokinesis. Between 6 to 10 months, they develop a cardiomyopathy that includes interstitial fibrosis and infiltration of the myocardium and pericardium with inflammatory cells. Four of 5 BMHC/BMHC hearts develop marked widening of intercalated discs.
Conclusions: By avoiding the embryonic lethality found in germline-ablated mice, we were able to study the function of NMII-B in adult mice and show that absence of NMII-B in cardiac myocytes results in cardiomyopathy in the adult heart. We also define a role for NMII-B in maintaining the integrity of intercalated discs.
Key words: nonmuscle myosin II-B • cardiomyopathy • intercalated discs