End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes.

Abstract

Proliferating cell nuclear antigen (PCNA) is a late growth-regulated gene that is expressed at the G1-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 human heart, we postulated that induction of the PCNA gene may be present in the failing heart in humans. PCNA protein was detected in myocardial samples obtained from the left and right ventricles of patients with congestive heart failure. Endomyocardial biopsies collected from donor subjects were used as control tissue. The percentage of positively stained myocyte nuclei in the ventricles was established by using PCNA monoclonal antibody and the immunoperoxidase technique. The localization of PCNA in myocytes was confirmed by alpha-sarcomeric actin antibody 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 percentage of PCNA-labeled myocyte nuclei was measured and found to constitute 49 +/- 22% of left ventricular myocytes. A similar analysis for the right ventricle, conducted in 21 patients, showed that 49 +/- 19% of the myocyte nuclei exhibited PCNA protein. In addition, mitotic figures in myocytes were documented. A quantitative analysis of this cellular process revealed that 11 myocyte nuclei per 1 million cells exhibited mitotic images in chronic heart failure. Immediately after myocardial infarction, two cells per million showed mitotic division, and this phenomenon was restricted to the region adjacent to the necrotic tissue. No PCNA labeling or nuclear mitotic images were detected in the ventricular myocardium of control subjects. Thus, the observation that diffuse PCNA labeling and myocyte mitotic division are present in hearts with end-stage failure strongly suggests that adult ventricular myocytes are not terminally differentiated cells and that myocyte cellular hyperplasia may constitute a growth reserve mechanism of the diseased heart.

Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

“…17 Interestingly, it has been reported in mammals that adaptive growth after heart injury through increase of cardiomyocyte size is associated with reactivation of cell cycle machinery as well as reexpression of a subset of fetal genes. [19][20][21][22][23][24][25] These observations suggest that cardiomyocytes initiate an abortive attempt to undergo cell division by dedifferentiation but the process is somehow hindered by negative regulators. This observation suggests that despite of the terminally differentiated status of adult mammalian cardiomyocytes, they are still able to dedifferentiate and proliferate.…”

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

“…In 1994, they demonstrated what appeared to be human cardiomyocytes undergoing mitosis in histologic sections of endomyocardial biopsies obtained from patients with chronic heart failure. 1 Cardiomyocytes in the regions surrounding damaged, necrotic areas were identified as mitotic by coexpression of proliferating cell nuclear antigen and α-sarcomeric actin. In a subsequent study, histologic sections of myocardium obtained from patients undergoing cardiac transplantation due to ischemic disease or dilated cardiomyopathy were labeled with propidium iodide and an α-sarcomeric actin antibody.…”

Hypoxic Preconditioning of Stem Cells as a New Approach to Increase the Efficacy of Cell Therapy for Myocardial Infarction

“…В норме митотический индекс для миокарда невелик и в миокарде мыши со-ставляет 0,0005% от числа всех кардиомиоцитов же-лудочков [7]. Для миокарда человека этот показатель составляет 11 делящихся кардиомиоцитов на 1 миллион клеток или 59 000 делящихся клеток в левом желудочке [8]. В экспериментальных исследованиях на животных было показано, что ИМ приводит к усилению пролифератив-ной активности кардиомиоцитов в периинфарктной зоне [9,10].…”