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

Background-Left ventricular hypertrophy (LVH) represents both an adaptive r esponse to increased cardiac work load and a precursor state of heart failu re. 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 apoptos is-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 surge ry, At this time point, we determined the occurrence of myocyte apoptosis b y DNA laddering, in situ DNA TUNEL labeling, and light and electron microsc opy. The monitoring of proapoptotic and antiapoptotic genes was determined by Western blot and immunohistochemistry. Our data demonstrated that cardio myocyte apoptotic events increased from virtually undetectable (in sham-ope rated controls, SH) to 0.8/10(3) and 1.5/10(3) positive nuclei in LVH and L VD, respectively. Fibrosis also increased in the subendocardial and midwall regions of LVH and LVD rats compared with SH. Expression of the proapoptot ic gene bar increased, whereas that of antiapoptotic gene bcl-2 decreased i n LVH and LVD compared with SH. Conclusions-These data suggest that in response to chronic pressure overloa d, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD, LVH and LVD were accompanied by a dramatic cardiomyocyte upregulati on of the proapoptotic gene bar and reduced bcl-2/bax ratio, predisposing c ardiomyocytes to apoptosis.