END-STAGE CARDIAC-FAILURE IN HUMANS IS COUPLED WITH THE INDUCTION OF PROLIFERATING CELL NUCLEAR ANTIGEN AND NUCLEAR MITOTIC DIVISION IN VENTRICULAR MYOCYTES
F. Quaini et al., END-STAGE CARDIAC-FAILURE IN HUMANS IS COUPLED WITH THE INDUCTION OF PROLIFERATING CELL NUCLEAR ANTIGEN AND NUCLEAR MITOTIC DIVISION IN VENTRICULAR MYOCYTES, Circulation research, 75(6), 1994, pp. 1050-1063
Proliferating cell nuclear antigen (PCNA) is a late growth-regulated g
ene that is expressed at the G(1)-S boundary of the cell cycle and is
required for DNA synthesis and cell proliferation. Since quantitative
results suggest that myocyte hyperplasia occurs in the decompensated h
uman heart, we postulated that induction of the PCNA gene may be prese
nt in the failing heart in humans. PCNA protein was detected in myocar
dial samples obtained from the left and right ventricles of patients w
ith congestive heart failure. Endomyocardial biopsies collected from d
onor subjects were used as control tissue. The percentage of positivel
y stained myocyte nuclei in the ventricles was established by using PC
NA monoclonal antibody and the immunoperoxidase technique. The localiz
ation of PCNA in myocytes was confirmed by alpha-sarcomeric actin anti
body staining. PCNA labeling was present in left ventricular myocytes
of 29 of the 32 hearts examined. In the right ventricle, 24 of the 29
samples showed positive staining. In a subset of 25 patients, the perc
entage of PCNA-labeled myocyte nuclei was measured and found to consti
tute 49 +/- 22% of left ventricular myocytes. A similar analysis for t
he right ventricle, conducted in 21 patients, showed that 49 +/- 19% o
f the myocyte nuclei exhibited PCNA protein. In addition, mitotic figu
res in myocytes were documented. A quantitative analysis of this cellu
lar process revealed that 11 myocyte nuclei per 1 million cells exhibi
ted mitotic images in chronic heart failure. Immediately after myocard
ial infarction, two cells per million showed mitotic division, and thi
s phenomenon was restricted to the region adjacent to the necrotic tis
sue. No PCNA labeling or nuclear mitotic images were detected in the v
entricular myocardium of control subjects. Thus, the observation that
diffuse PCNA labeling and myocyte mitotic division are present in hear
ts with end-stage failure strongly suggests that adult ventricular myo
cytes are not terminally differentiated cells and that myocyte cellula
r hyperplasia may constitute a growth reserve mechanism of the disease
d heart.