(Circulation. 2000;101:2854.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Left Ventricular Hypertrophy in Ascending Aortic Stenosis Mice
Anoikis and the Progression to Early Failure
From the Harvard-Thorndike Laboratory and the Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (B.D., X.Y., P.S.D., E.O.W., J.B., B.H.L.); the Department of Developmental Biology and Anatomy, University of South Carolina School of Medicine, Columbia (R.L.P., E.C.G., T.K.B., T.T.); and the Department of Neurosurgery, Baylor College of Medicine, Houston, Tex (V.V.D.).
Correspondence to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail blorell{at}caregroup.harvard.edu
Background—To determine potential mechanisms of the transition from hypertrophy to very early failure, we examined apoptosis in a model of ascending aortic stenosis (AS) in male FVB/n mice.
Methods and Results—Compared with age-matched controls, 4-week and 7-week AS animals (n=12 to 16 per group) had increased ratios of left ventricular weight to body weight (4.7±0.7 versus 3.1±0.2 and 5.7±0.4 versus 2.7±0.1 mg/g, respectively, P<0.05) with similar body weights. Myocyte width was also increased in 4-week and 7-week AS mice compared with controls (19.0±0.8 and 25.2±1.8 versus 14.1±0.5 µm, respectively, P<0.01). By 7 weeks, AS myocytes displayed branching with distinct differences in intercalated disk size and staining for ß1-integrin on both cell surface and adjacent extracellular matrix. In vivo left ventricular systolic developed pressure per gram as well as endocardial fractional shortening were similar in 4-week AS and controls but depressed in 7-week AS mice. Myocyte apoptosis estimated by in situ nick end-labeling (TUNEL) was extremely rare in 4-week AS and control mice; however, a low prevalence of TUNEL-positive myocytes and DNA laddering were detected in 7-week AS mice. The specificity of TUNEL labeling was confirmed by in situ ligation of hairpin oligonucleotides.
Conclusions—Our findings indicate that myocyte apoptosis develops during the transition from hypertrophy to early failure in mice with chronic biomechanical stress and support the hypothesis that the disruption of normal myocyte anchorage to adjacent extracellular matrix and cells, a process called anoikis, may signal apoptosis.
Key Words: myocytes • hypertrophy • heart failure • integrins • apoptosis
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