doi: 10.1161/01.RES.0000233141.65522.3e
© 2006 American Heart Association, Inc.
Editorials |
Diabetic Cardiomyopathy
A "Cardiac Stem Cell Disease" Involving p66Shc, an Attractive Novel Molecular Target for Heart Failure Therapy
From the Department of Experimental Medicine and Pathology, University of Rome "La Sapienza", Rome, Italy.
Correspondence to Dr Alessandro Giacomello, University of Rome "la Sapienza", Experimental Medicine and Pathology, viale Regina Elena 324, Rome 00161, Italy. E-mail alessandro.giacomello{at}uniroma1.it
See related article, pages 42–52
Key Words: diabetes • cardiac stem cells • p66Shc
Diabetes, as well as hypertension and aging, have similar effects on heart dysfunction, resulting in left ventricular hypertrophy and stiffness. These three pathological states share two common points of no return: oxidative stress and ROS formation.
Research in this area is not new. For the past 30 to 40 years, basic and pharmacological research has focused on efforts to block the production or counteract the effects of these highly reactive, unstable molecules. It is only in the last few years that, their direct toxic role in cellular structures notwithstanding, ROS has been regarded as a second messenger.1 This represents a more subtle and insidious mechanism of action, because their byproduct and amplified effects may depend on activated cascades leading to persistent consequences (apoptosis, necrosis), even if ROS are naturally or pharmacologically contrasted.
In this regard the adaptor protein p66Shc, which along with p46Shc and p52Shc, is encoded by the ShcA gene, has been demonstrated to be a target of ROS.2 p46Shc and p52Shc are ubiquitous isoforms, derived from the same mRNA through alternative start sites.3 In contrast, p66Shc expression is restricted to certain cell types and stimulatory conditions through epigenetic modifications of its distinct promoter.4–5 Shc is tyrosine-phosphorylated in response to growth factors and Ang II.2–6 Once phosphorylated, Shc forms a complex with Grb2, recruiting the Son-of-sevenless (SOS) exchange protein to the plasma membrane for activation of Ras. The three Shc isoforms have distinct physiological roles. In particular, whereas both p46Shc and p52Shc promote cellular proliferation and differentiation via Ras and MAP kinases, p66Shc inhibits Ras/ERK signaling and blunts mitogenic responses, at least in part by competing with p52Shc for a limited pool of Grb2. Furthermore, p66Shc sensitizes cells to apoptosis in response to oxidative stress through a mechanism that involves a phosphorylation event at S36.7 The phosphorylation-induced repression of Forkhead transcription factors (which regulate the expression of several antioxidant enzymes), and the activation of p66 mitochondrial pool (leading the induction of mPTP opening and cytochrome C release), represent the main pathways involved in the contribution of this protein to the cellular sensitization to ROS-induced apoptosis.8,9 p66Shc knockout mice have shown an increased resistance to oxidative stress, a 30% increase in life span, and a resistance to the deleterious remodeling effects of a subpressor dose of Ang II.2 Therefore the ROS formation scenario in heart failure has been enriched by a new molecular target (p66Shc).
Rota et al report in this issue of Circulation Research that the ablation of the p66shc gene prevents whole heart pathophysiological consequences of oxidative stress with streptozotocin (STZ)-induced diabetes in mice.10 Moreover the authors show that the unfavorable effects on cardiac stem/progenitor cells (CSCs), such as their numeric reduction and telomeric shortening (expression of cellular senescence), are not observed in the transgenic KO mice. Rota et al further demonstrate that exposure of high glucose to the isolated CSCs from diabetic WT, but not p66Shc–/–, induces the generation of ROS and apoptosis. A low or intermediate level of ROS causes proliferation of CSCs and a high level of ROS causes apoptosis or necrosis of CSCs.
The recognition that p66Shc conditions the destiny of CSCs raises the possibility that diabetic cardiomyopathy is a stem cell disease, in which abnormalities in CSCs define the life and death of the heart. Rota et al, in fact, conclude that diabetic cardiomyopathy could be considered a "stem cell disease."
Diabetes is a significant risk factor for cardiovascular morbidity and mortality, mainly through a procoagulant state and accelerated atherosclerosis leading to a coronaric disease. Moreover, diabetic cardiomyopathy is one of the common causes of heart failure, but the mechanism of the cardiac dysfunction is multifaceted and unclear. Interestingly, the protective effects of p66Shc ablation have been reported in EPCs as well,11 and many studies identify p66Shc as a critical transducer of oxidative stress signals. Thus the preserved cardiac function observed in the p66shc–/– mice could also reflect the general beneficial effect of the reduction of ROS production and action.
Rota et al, however, focused on the consequences of hyperglycemia as a ROS-generating system that can participate in the activation of p66Shc in cardiac myocytes in general, and in cardiac stem cells in particular. It is in these cells, in fact, that the effects of the protein may achieve their more deleterious consequences in terms of senescence and apoptosis. The effective level and modulation of p66shc in cardiac stem cells, however, have not been studied in depth.
Although p52Shc is detected in various cardiac cell preparations, p66Shc is readily detected in neonatal cardiomyocytes, but it is at the limits of detection in the adult ventricle. The expression of this protein is low and apparently ubiquitary in normal heart, but increases in a pacing model of heart failure in the dog, in association with an increase in cardiomyocyte apoptosis.12 The relative contribution of p66 to heart tissue damage in response to oxidative stress may reflect individual expression differences. Further studies should be performed to asses p66Shc levels in cardiac cells from diabetic patients.
A recent study has identified a novel regulation of individual Shc isoforms in receptor-dependent pathways leading to cardiac hypertrophy and the transition to heart failure.7 The observation that p66Shc expression is induced by a G
q agonist, and that PAR-1 activation leads to p66Shc-S36, identifies p66Shc as a novel candidate for a hypertrophy-induced mediator of cardiomyocyte apoptosis and heart failure. This same observation also confirms that p66Shc is an attractive novel molecular target for heart failure therapy.
Some of the coauthors of Rota et al are the same investigators who first suggested the existence of cardiac myocytes renewal, and described for the first time the existence of a resident population of cardiac stem cells that, as in other organs, maintains the equilibrium between cell death and regeneration.13–14 In this view it is logical to attribute to CSC damage a "prima donna" role in the pathophysiology of diabetic cardiomyopaty.
Other stem-progenitor cells (HSC, NCS, and EPC) have been described to be primarily involved in the pathophysiological sequelae of oxidative stress.11,15,16 However, this article by Rota et al represents the first time that CSC-specific damage has been recognized as a cause–effect mechanism specifically for cardiac disease. In the pathophysiology of diabetic cardiomyopathy in particular, and in heart failure in general, a strategic link has been introduced here between CSCs and p66Shc, a link that crosses between life span and senescence at cellular and molecular level. The article by Rota et al suggests that the level of p66Shc should be the critical factor for the preservation of equilibrium and vitality in cardiac cells. One consequence is that p66Shc levels or activation could inhibit maintenance of CSC quiescence, and affect the stemness function in vivo. Based on previously published data, and the data presented in this issue by Rota et al, it is reasonable to surmise that the ROS–p66Shc pathway may be involved in the pathophysiology of CSC senescence in normal aging, in hypertension, and in CSC exhaustion observed in diabetic mice. The characterization of the molecular mechanisms that limit CSCs lifespan may lead to beneficial therapies for human disease.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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