The recognition that the heart possesses a stem cell compartment that forms myocytes and coronary vessels raises the possibility that alterations in number and/or function of cardiac progenitor cells (CPCs) condition the onset of the aging myopathy. The decline in regenerative capacity of resident CPCs may dictate the accumulation of old myocytes and the cardiac senescent phenotype. The life cycle of CPCs appears to be regulated by telomerase activity and telomere length;shortening of telomeres beyond a critical length triggers cellular senescence and death. Although the role of telomere attrition in cellular aging has been documented in vitro, it remains to be determined whether loss of telomere DNA leads to organ and organism aging in vivo. Thus, our major goal is to assess whether: a) telomere shortening occurs during myocardial aging in vivo;b) CPCs with critically short telomeres undergo replicative senescence and apoptosis;and c) telomere shortening causes stem cell and myocyte aging and ultimately heart failure. We will attempt to answer these questions by employing first an animal model in which telomere erosion depends on the deletion of the RNA component of telomerase. Subsequently, we will study the telomerase-telomere axis in human CPCs (hCPCs) and establish whether telomerase activity and telomere length modulate the growth properties of these cells. Evidence in our laboratory suggests that IGF-1 prevents telomere attrition and enhances telomerase activity while Ang II promotes oxidative stress in hCPCs. Therefore, IGF-1 receptor (IGF-1R) and Ang II receptor 1 (AT1R) will be employed to isolate hCPCs with long and short telomeres, respectively. The function of IGF-1R and AT1R in hCPCs may be mediated by their opposite effects on the expression and activity of p53;p53 is expected to be critically involved in hCPC senescence. Whether p53-responsive genes dictate hCPC senescence and cardiac aging is currently unknown. We will focus on the interaction between p53, miR-34 and miR-34 target genes;miR-34 is a downstream effector of p53 and is proposed to be an important determinant of CPC and cardiac aging.
Senescence of cardiac progenitor cells is a critical determinant of the aging myopathy. A new approach is proposed here for the identification of progenitor cells which may have a significant capacity to divide and form a large number of cardiomyocytes. If successful, this strategy may have important implications for the management of human heart failure in the elderly.
| Borghetti, Giulia; Eisenberg, Carol A; Signore, Sergio et al. (2018) Notch signaling modulates the electrical behavior of cardiomyocytes. Am J Physiol Heart Circ Physiol 314:H68-H81 |
| Kannappan, Ramaswamy; Matsuda, Alex; Ferreira-Martins, João et al. (2017) p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo. EBioMedicine 16:224-237 |
| Meo, Marianna; Meste, Olivier; Signore, Sergio et al. (2016) Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm. J Am Heart Assoc 5: |
| Sorrentino, Andrea; Signore, Sergio; Qanud, Khaled et al. (2016) Myocyte repolarization modulates myocardial function in aging dogs. Am J Physiol Heart Circ Physiol 310:H873-90 |
| Signore, Sergio; Sorrentino, Andrea; Borghetti, Giulia et al. (2015) Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy. Nat Commun 6:8803 |
| Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article ""Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes"". Circulation 129:e510-1 |
| Iso, Yoshitaka; Rao, Krithika S; Poole, Charla N et al. (2014) Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction. Stem Cells 32:674-83 |
| Goichberg, Polina; Chang, Jerway; Liao, Ronglih et al. (2014) Cardiac stem cells: biology and clinical applications. Antioxid Redox Signal 21:2002-17 |
| D'Amario, Domenico; Leone, Antonio M; Iaconelli, Antonio et al. (2014) Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery. Circulation 129:157-72 |
| Leri, Annarosa; Rota, Marcello; Hosoda, Toru et al. (2014) Cardiac stem cell niches. Stem Cell Res 13:631-46 |
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