(Circulation. 1999;99:3071-3078.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Increased Cardiomyocyte Apoptosis and Changes in Proapoptotic and Antiapoptotic Genes bax and bcl-2 During Left Ventricular Adaptations to Chronic Pressure Overload in the Rat
From Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pa (G.C., R.R.); the Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy (G.C.); the Department of Cardiology, I.R.C.C.S., INM "Neuromed," Pozzilli (IS) (G.C., C.M., A.N., G. Sgaramella, A.d.R., B.T., G.L.); the Department of Internal Medicine, "Federico II" University, Naples, Italy (B.T., G.L.); Children's Hospital of Pittsburgh, Rangos Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pa (G. Stassi); and the Department of Surgical, Anatomical, and Oncological Sciences, Anatomy Section, University of Palermo, Italy (G. Stassi, F.F.).
Correspondence to Gianluigi Condorelli, MD, PhD, Kimmel Cancer Center (Room 1006), 233 S 10th St, Philadelphia PA, 19107. E-mail condore1{at}jeflin.tju.edu
Background—Left ventricular hypertrophy (LVH) represents both an adaptive response to increased cardiac work load and a precursor state of heart failure. Recent evidence linked cardiac myocyte death by apoptosis with LVH and heart failure. It remained unclear, however, whether apoptosis participated in the transition from LVH to left ventricular dysfunction (LVD).
Methods and Results—Cardiac myocyte apoptotic events and changes in apoptosis-specific genes were studied in a rat model of chronic pressure overload induced by transverse aortic constriction. The changes in left ventricular geometry and function were assessed by echocardiography. Transverse aortic constriction rats progressively developed "concentric" LVH and subsequently, LVD. A similar distribution of LVH and LVD was found 18 weeks after surgery. At this time point, we determined the occurrence of myocyte apoptosis by DNA laddering, in situ DNA TUNEL labeling, and light and electron microscopy. The monitoring of proapoptotic and antiapoptotic genes was determined by Western blot and immunohistochemistry. Our data demonstrated that cardiomyocyte apoptotic events increased from virtually undetectable (in sham-operated controls, SH) to 0.8/103 and 1.5/103 positive nuclei in LVH and LVD, respectively. Fibrosis also increased in the subendocardial and midwall regions of LVH and LVD rats compared with SH. Expression of the proapoptotic gene bax increased, whereas that of antiapoptotic gene bcl-2 decreased in LVH and LVD compared with SH.
Conclusions—These data suggest that in response to chronic pressure overload, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD. LVH and LVD were accompanied by a dramatic cardiomyocyte upregulation of the proapoptotic gene bax and reduced bcl-2/bax ratio, predisposing cardiomyocytes to apoptosis.
Key Words: cells • heart failure • genes • apoptosis • hypertrophy
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