© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Apoptosis
aJanssen Research Foundation, Beerse, Belgium
bCARIM, Maastricht University, Maastricht, The Netherlands
cDepartment of Medicine, University of Turku, Turku, Finland
dBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
* Corresponding author
Received 11 November 1999; accepted 11 November 1999
This spotlight issue on apoptosis in the cardiovascular system appears at a point in time at which enough solid evidence has emerged to convince the most critical investigator of the prevalence of the phenomenon in most of the important cardiac and vascular diseases. The aim of this issue is, first, to give the cardiovascular investigator an introduction and overview with reference to the vast literature dealing with myocardial and vascular apoptosis and, second, to include a number of highly qualified original papers on this topic.
By way of accomplishing these two aims, the issue is organised into the following six sections:
1. Detection and Basic Mechanisms of Apoptosis.
The section opens with a paper by Saraste and Pulkki [1] that reviews the current knowledge on the molecular mechanisms of apoptosis as they relate to morphologic hallmarks and their implications for the detection of apoptosis in cardiac tissue. Of special interest are guidelines on detecting true apoptosis and eliminating false positives and false negatives. The second review, by Depré and Taegtmeyer [2], deals with the metabolic aspects of apoptosis. In this review a clear distinction is made in terms of metabolic imprints and energetic aspects, between myocardial necrosis (infarction), failing heart (programmed cell death), and preconditioning, stunning and hibernation (which the authors call programmed cell survival).
The paper by van Heerde et al. [3], in addition to briefly reviewing the available techniques for the detection and quantification of apoptosis by light and electron microscopy, focuses on the recently introduced Annexin V-based apoptosis detection assay.
The last review in this section is by Feuerstein and Young [4], who highlight the role of protein kinase-signalling pathways in cardiomyocyte apoptosis, with special attention to MAPK and SAPK. A few examples of possible anti-apoptotic therapies are given.
Four original articles appear in this section. The first, by Perlmann et al. [5], establishes the essential role of Bcl-2 in vascular smooth muscle cell viability. Huber [6] presents evidence that in experimental models mimicking myocarditis and dilated cardiomyopathy, apoptosis is induced in cardiomyocytes by T cells expressing the 
T cell receptor. The study by Taimor et al. [7] characterizes the pathway of induction of apoptosis by NO and the influence of ischaemia on this pathway in cardiomyocytes. The section closes with an investigation by Song et al. [8], who tested the hypothesis that TNF
induces myocardial apoptosis by induction of iNOS expression and NO production.
2. Section II is on Apoptosis in Cardiovascular Development and contains two review papers. The first one, by van den Hoff et al. [9], is a detailed descriptive review of the functional role of cell death, and in particular apoptosis, during development of the heart. The usefulness of Annexin V in detecting apoptosis during development is given special attention.
In the second review, Revzani et al. [10] discuss apoptosis-related genes expressed in cardiovascular development and disease. Identifying key genes involved in the regulatory process of apoptosis provides the basis for creating effective therapeutics in disease as well as a better understanding of how cardiac development is modulated. Especially the usefulness of expressed sequence tags (ESTs) is emphasized.
3. Section III, titled Apoptosis in Ischaemia and Infarction, contains one review and five original papers. The review by Yaoita et al. [11] provides an update on the role of apoptotic removal of various cell types during tissue repair after infarction. The authors critically assess the validity of classical morphological assays, such as TUNEL, used to detect apoptosis. They also discuss the role of anti-apoptotic therapy in infarct-size reduction. Okamura et al. [12] address the same question by studying the effect of caspase inhibitors on the final outcome of infarct size. The problem of injury due to ischaemia/reperfusion and its relation to apoptosis is addressed by Thao et al. [13], who relate the apoptotic event to changes in expression of Bcl-2 and Bax, In a second paper by the same group, Nakumura et al. [14] propose that ischaemic preconditioning reduces myocardial apoptosis by inhibiting PMN accumulation and attenuated Bax expression. The paper by Weiland et al. [15] deals with the role of endogenous NO during ischaemia/reperfusion and suggests that inhibition of endogenous NOS induces apoptosis through a caspase-3 dependent pathway. Finally, Oskarsson et al. [16] describe the role of anti-oxidant therapy in the attenuation of myocyte apoptosis in areas remote from large infarcted zones.
4. Section IV, titled Apoptosis in Hypertrophy, Hibernation and Heart Failure, consists of four reviews and two original articles.
The review by Sach et al. [17] is the only one that (partially) deals with hypertrophic response, and this in a very peculiar way. The authors focus their mini-review on the role of TNF in mediating myocardial cell survival, growth and differentiation as adaptation responses to acute and subacute biomechanical stress, rather than emphasizing its role in apoptosis. The second paper, by Dispersyn et al. [18], reviews the limited literature available on apoptosis in hibernating myocardium and critically questions whether apoptosis plays a major role under the condition when all the criteria for hibernation are fulfilled. Two reviews follow on the failing heart. The first is by Sabbah [19], who gives a comprehensive overview of the clinical and experimental data in heart failure. At the same time, Sabbah tries to critically balance apoptotic findings by presenting ‘realistic’ quantitative estimates of the apoptotic incidence in cardiac pathologies. The review by Singh et al. [20] discusses in depth adrenergic regulation of myocardial apoptosis, in particular its role in the development of myocardial failure. Two original papers on heart failure follow these reviews. The first is by Schumann et al. [21], who compare samples derived from failing and non-failing hearts for the differential expression of secreted Frizzled Related Proteins (sFRP3 and 4) in relation to apoptosis-related gene expression. The second is by Liu et al. [22] and concerns the presence of increased apoptosis in the hearts of animals with genetic hypertension, the involvement of fibroblasts and the inhibiting effect of ACE inhibitors on apoptosis.
5. Section V is titled Apoptosis in Vascular Disease.
This section, which at first glance addresses a less controversial area in cardiovascular apoptosis, contains three reviews and four original articles. It opens with a review by Kockx and Herman [23], provocatively titled ‘Apoptosis in Atherosclerosis: Beneficial or Detrimental?’. The authors, who are well known for their critical assessment of apoptosis detection in the vessel wall, review the literature on atherosclerosis from an unbiased perspective as to benefit or harm when apoptosis occurs in the atherosclerotic plaque. Their idea that apoptosis of smooth muscle cells might contribute to plaque instability deserves special attention.
A more general and well-balanced approach to the role of apoptotic vascular pathology is given in the review on regulation of vascular smooth muscle cell apoptosis by McCarthy and Bennett [24], in which special attention is given to the particular sensitivity of some tissues or sites to apoptotic stimuli. The authors attribute this sensitivity to possible defects in survival signalling pathways or to a defect in the regulation of cell cycle control. A third, very complementary review by Walsh and Isner [25] addresses apoptosis in inflammatory-fibroproliferative disorders of the vessel wall, such as atherosclerotic and restenotic lesions. The authors propose that apoptosis plays a role in controlling the viability of inflammatory and vascular cells, thereby determining the cellular composition of the vessel wall.
The first original article is by Kamenz et al. [26] and describes the incidence of intimal thickening and apoptosis after balloon angioplasty in an experimental model. This paper is followed by an article by Holm et al. [27], who suggest that ACE inhibition leads to attenuated intimal thickening in a model of carotid artery injury by an apoptotic mechanism.
Suzuki et al. [28], in studying the fate of cardiac allografts, show that antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation. The last contribution to this section is by Romeo et al. [29] and presents data on the induction of apoptosis by epinephrine in human coronary artery endothelial cells, the effects of which are counteracted by β-adrenergic antagonists, possibly related to their anti-oxidant properties.
6. The closing section consists of a review by Haunstetter and Izumo [30] and is titled Future Perspectives and Potential Implications of Cardiomyocyte Apoptosis. The authors concentrate on unravelling the links between recently gained insights into the molecular mechanisms of apoptosis and the related cardiac pathology.
We hope that this spotlight issue has fulfilled some expectations as to its pre-set goal, which was to resolve some of the current confusion (in reality, resistance and negligence) about the existence and significance of apoptosis in the heart, and to a lesser extent, in the vascular wall. More important, we hope that the advances in our understanding of apoptotic mechanisms may lead to new therapies for important cardiac and vascular diseases. In this respect, one might be better off paying more attention to factors that regulate programmed cell survival than to those that regulate programmed cell death.
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- Saraste A, Pulkki K. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res (2000) 45:528.
[Abstract/Free Full Text] - Depré C, Taegtmeyer H. Metabolic aspects of programmed cell survival and cell death in the heart. Cardiovasc Res (2000) 45:538.
[Abstract/Free Full Text] - van Heerde W.L, Robert-Offerman S, Dumont E, Hofstra L, Doevendans P.A, Smits J.F.M, et al. Markers of apoptosis in cardiovascular tissues. Cardiovasc Res (2000) 45:549.
[Abstract/Free Full Text] - Feuerstein G.Z, Young P.R. Apoptosis in cardiac diseases: stress and mitogen activated signalling pathways. Cardiovasc Res (2000) 45:560.
[Abstract/Free Full Text] - Perlmann H, Masataka S, Krasinski K, Doral T, Buttyan R, Walsh K. Adenovirus-encoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis. Cardiovasc Res (2000) 45:570.
[Abstract/Free Full Text] - Huber S.A. T cells expressing the gamma-delta T cell receptor induce apoptosis in cardiac myocytes. Cardiovasc Res (2000) 45:579.
[Abstract/Free Full Text] - Taimor G, Hofstaetter B, Piper H.M. Apoptosis induction by NO in adult cardiomyocytes via cGMP-signalling and its impairment after simulated ischemia. Cardiovasc Res (2000) 45:588.
[Abstract/Free Full Text] - Song W, Lu X, Feng Q. Tumor necrosis factor – alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes. Cardiovasc Res (2000) 45:595.
[Abstract/Free Full Text] - van den Hoff M, van den Eijnde S.M, Virágh S, Moorman A. Programmed cell death in the developing heart. Cardiovasc Res (2000) 45:603.
[Free Full Text] - Rezvani M, Barrans J.D, Dai K.S, Liew C.C. Apoptosis-related genes expressed in cardiovascular development and disease: an EST approach. Cardiovasc Res (2000) 45:621.
[Abstract/Free Full Text] - Yaoita H, Ogawa K, Maehara K, Maruyama Y. Apoptosis in relevant clinical situations – contribution of apoptosis in myocardial infarction. Cardiovasc Res (2000) 45:630.
[Abstract/Free Full Text] - Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Matsuzaki, et al. Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res (2000) 45:642.
[Abstract/Free Full Text] - Zhao Z.-Q, Nakamura M, Wang N.-P, Wilcox J.N, Vinten-Johansen J, Shearer S, et al. Reperfusion induces myocardial apoptotic cell death. Cardiovasc Res (2000) 45:651.
[Abstract/Free Full Text] - Nakamura M, Wang N.-P, Zhao Z.-Q, Wilcox J.N, Thourani V.H, Guyton R.A, Vinten-Johansen J. Inhibition of endogenous nitric oxide synthase potentiates ischemial reperfusion induced myocardial apoptosis via a caspase-3 dependent pathway. Cardiovasc Res (2000) 45:661.
[Abstract/Free Full Text] - Weiland U, Haendeler J, Ihling C, Albus U, Scholz W, Dimmeler S, et al. Preconditioning decreases bax expression. PMN accumulation and apoptosis in reperfused rat heart. Cardiovasc Res (2000) 45:671.
[Abstract/Free Full Text] - Oskarsson H.J, Coppey L, Weiss R.M, Li W.G. Antioxidants attenuate myocyte apoptosis in the remote non-infarcted myocardium following large myocardial infarction. Cardiovasc Res (2000) 45:679.
[Abstract/Free Full Text] - Sack M.N, Smith R.M, Opie L.H. Tumor necrosis factor in myocardial hypertrophy and ischaemia – an anti-apoptotic perspective. Cardiovasc Res (2000) 45:688.
[Free Full Text] - Dispersyn G.D, Borgers M, Flameng W. Apoptosis in chronic hibernating myocardium: sleeping to death? Cardiovasc Res (2000) 45:696.
[Abstract/Free Full Text] - Sabbah H.N. Apoptotic cell death in heart failure. Cardiovasc Res (2000) 45:704.
[Free Full Text] - Singh K, Communal C, Sawyer D.B, Colucci W. Adrenergic regulation of myocardial apoptosis. Cardiovasc Res (2000) 45:713.
[Abstract/Free Full Text] - Schumann H, Holtz J, Zerkowski H.-R, Hatzfeld M. Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression. Cardiovasc Res (2000) 45:720.
[Abstract/Free Full Text] - Liu J.J, Peng L, Bradley C.J, Zulli A, Shen J, Buxton B.F. Increased apoptosis in the heart of genetic hypertension, associated with increased fibroblasts. Cardiovasc Res (2000) 45:729.
[Abstract/Free Full Text] - Kockx M.M, Herman A.G. Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res (2000) 45:736.
[Abstract/Free Full Text] - McCarthy N.J, Bennett M.R. The regulation of vascular smooth muscle cell apoptosis. Cardiovasc Res (2000) 45:747.
[Abstract/Free Full Text] - Walsh K, Isner J.M. Apoptosis in inflammatory-fibroproliferative disorders of the vessel wall. Cardiovasc Res (2000) 45:756.
[Abstract/Free Full Text] - Kamenz J, Seibold W, Wohlfrom M, Hanke S, Heise N, Lenz C, Hanke H. Incidence of intimal proliferation and apoptosis following balloon angioplasty in an atherosclerotic rabbit model. Cardiovasc Res (2000) 45:766.
[Abstract/Free Full Text] - Holm A.M, Andersen C.B, Haunso S, Hansen P.R. ACE-inhibition promotes apoptosis after balloon injury or rat carotid arteries. Cardiovasc Res (2000) 45:777.
[Abstract/Free Full Text] - Suzuki J, Isobe M, Morishita R, Nishikawa T, Amano J, Kaneda Y. Antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation in murine cardiac allografts. Cardiovasc Res (2000) 45:783.
[Abstract/Free Full Text] - Romeo F, Li D, Shi M, Mehta J.L. Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells. Cardiovasc Res (2000) 45:788.
[Abstract/Free Full Text] - Haunstetter A, Izumo S. Future perspectives and potential implications of cardiac myocyte apoptosis. Cardiovasc Res (2000) 45:795.
[Abstract/Free Full Text]
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