Showing papers by "Annarosa Leri published in 2010"

Intracoronary Administration of Cardiac Progenitor Cells Alleviates Left Ventricular Dysfunction in Rats With a 30-Day-Old Infarction

Abstract: Background— Administration of cardiac progenitor cells (CPCs) 4 hours after reperfusion ameliorates left ventricular function in rats with acute myocardial infarction (MI) Clinically, however, this approach is not feasible, because expansion of autologous CPCs after acute MI requires several weeks Therefore, we sought to determine whether CPCs are beneficial in the more clinically relevant setting of an old MI (scar) Methods and Results— One month after coronary occlusion/reperfusion, rats received an intracoronary infusion of vehicle or enhanced green fluorescent protein–labeled CPCs Thirty-five days later, CPC-treated rats exhibited more viable myocardium in the risk region, less fibrosis in the noninfarcted region, and improved left ventricular function Cells that stained positive for enhanced green fluorescent protein that expressed cardiomyocyte, endothelial, and vascular smooth muscle cell markers were observed only in 7 of 17 treated rats and occupied only 26% and 11% of the risk and noninfa

Cardiomyogenesis in the Adult Human Heart

Abstract: Rationale: The ability of the human heart to regenerate large quantities of myocytes remains controversial, and the extent of myocyte renewal claimed by different laboratories varies from none to nearly 20% per year. Objective: To address this issue, we examined the percentage of myocytes, endothelial cells, and fibroblasts labeled by iododeoxyuridine in postmortem samples obtained from cancer patients who received the thymidine analog for therapeutic purposes. Additionally, the potential contribution of DNA repair, polyploidy, and cell fusion to the measurement of myocyte regeneration was determined. Methods and Results: The fraction of myocytes labeled by iododeoxyuridine ranged from 2.5% to 46%, and similar values were found in fibroblasts and endothelial cells. An average 22%, 20%, and 13% new myocytes, fibroblasts, and endothelial cells were generated per year, suggesting that the lifespan of these cells was approximately 4.5, 5, and 8 years, respectively. The newly formed cardiac cells showed a full...

Myocyte Turnover in the Aging Human Heart

Abstract: Rationale The turnover of cardiomyocytes in the aging female and male heart is currently unknown, emphasizing the need to define human myocardial biology. Objective The effects of age and gender on the magnitude of myocyte regeneration and the origin of newly formed cardiomyocytes were determined. Methods and results The interaction of myocyte replacement, cellular senescence, growth inhibition, and apoptosis was measured in normal female (n=32) and male (n=42) human hearts collected from patients 19 to 104 years of age who died from causes other than cardiovascular diseases. A progressive loss of telomeric DNA in human cardiac stem cells (hCSCs) occurs with aging and the newly formed cardiomyocytes inherit short telomeres and rapidly reach the senescent phenotype. Our data provide novel information on the superior ability of the female heart to sustain the multiple variables associated with the development of the senescent myopathy. At all ages, the female heart is equipped with a larger pool of functionally competent hCSCs and younger myocytes than the male myocardium. The replicative potential is higher and telomeres are longer in female hCSCs than in male hCSCs. In the female heart, myocyte turnover occurs at a rate of 10%, 14%, and 40% per year at 20, 60, and 100 years of age, respectively. Corresponding values in the male heart are 7%, 12%, and 32% per year, documenting that cardiomyogenesis involves a large and progressively increasing number of parenchymal cells with aging. From 20 to 100 years of age, the myocyte compartment is replaced 15 times in women and 11 times in men. Conclusions The human heart is a highly dynamic organ regulated by a pool of resident hCSCs that modulate cardiac homeostasis and condition organ aging.

Anthracycline Cardiomyopathy Is Mediated by Depletion of the Cardiac Stem Cell Pool and Is Rescued by Restoration of Progenitor Cell Function

Abstract: Background— Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases; however, they have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure. Methods and Results— Administration of doxorubicin in rats led to a dilated myopathy, heart failure, and death. To test whether the effects of doxorubicin on cardiac anatomy and function were mediated by alterations in cardiac progenitor cells (CPCs), these cells were exposed to the anthracycline, which increased the formation of reactive oxygen species and caused increases in DNA damage, expression of p53, telomere attrition, and apoptosis. Additionally, doxorubicin resulted in cell-cycle arrest at the G2/M transition, which led to a significant decrease in CPC growth. Doxorubicin elicited multiple molecular adaptations; the massive apoptotic death that occurred in CPCs in the presence of anthracycline imposed on the surviving CPC pool th...

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

Abstract: Background— Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of β-amyloid impair cell function and lead to cell death. Methods and Results— We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca2+ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions— On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca2+ handling and a direct effect...

Mechanisms of Myocardial Regeneration

Abstract: The plasticity of bone marrow-derived progenitor cells (BMPCs) and their ability to acquire the myocyte lineage and regenerate dead myocardium after infarction has been challenged. Similarly, although several laboratories have identified cardiac progenitor cells (CPCs), the controversy concerning myocyte regeneration in the adult heart has not been resolved. The therapeutic efficacy of these 2 classes of progenitor cells depends on their ability to (1)survive in the hostile milieu of the damaged heart, (2)engraft within the myocardium and (3)grow and differentiate. BMPCs may have a growth potential that is superior to that of CPCs, but transdifferentiation could affect this characteristic and CPCs may constitute a more powerful form of therapy for cardiac repair. The process of transdifferentiation may alter the growth behavior of BMPCs, which may result in losing part of their capability of dividing through alterations of the telomere-telomerase system, premature cellular senescence and apoptosis. Moreover, myocytes derived from BMPCs may possess inherent limitations in the acquisition of the adult phenotype. The opposite may also be true and BMPCs may retain a stronger regenerative capacity than CPCs, representing the most appropriate cells for the damaged heart even after transdifferentiation. Ultimately, the question to be addressed is whether BMPCs are superior, equal or inferior to CPCs for the regeneration of cardiomyocytes and coronary vessels in acute and chronic ischemic heart failure. (Circ J 2010; 74: 13 - 17).

Inhibition of Notch1-Dependent Cardiomyogenesis Leads to a Dilated Myopathy in the Neonatal Heart

Abstract: Rationale: Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. Objective: In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment. Methods and Results: We have found that the newborn heart contains a population of c-kit–positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a γ-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored. Conclusions: Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.

Increasing Cardiac Contractility After Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction

Abstract: Rationale:Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study. Objectives:We developed a mouse model in which we could prevent depressed myocyte contractility after MI and used it to test the idea that preventing depression of myocyte Ca2+-handling defects could avert post-MI cardiac pump dysfunction. Methods and Results:MI was produced in mice with inducible, cardiac-specific expression of the β2a subunit of the L-type Ca2+ channel. Myocyte and cardiac function were compared in control and β2a animals before and after MI. β2a myocytes had increased Ca2+ current; sarcoplasmic reticulum Ca2+ load, contraction and Ca2+ transients (versus controls), and β2a hearts had increased performance before MI. After MI, cardiac function decreased. However, ventricular dilation, myocyte hypertrophy and death, and depressed cardiac...

Treatment of heart disease

Abstract: Disclosed herein are methods, compositions and kits for treating cardiac stem cells to be administered to a subject in need thereof, e.g., with a damaged myocardium. The methods, composition and kits of the invention can be used to treat cardiovascular diseases such as heart failure, myocardial infarction and an age-related cardiomyopathy.

Cardiac Regeneration and Aging

Abstract: Publisher Summary This chapter discusses inability of the mammalian heart to regenerate parenchymal cells, that is, decrease in the number of ventricular myocytes which results in aging and cardiac diseases The effects of age and pathological states on the number of tissue-specific cell types are similar in organs with high- or low-turnover cell rates In myocardium, adaptation to stress involves an increased replicative response that does not maintain tissue homeostasis, since cell death exceeds cell division (Kempermann et al, 2004; Urbanek et al, 2005) The behavior of the heart, therefore, corresponds to a model of tissue growth essentially common to all organs in the organism Chronological age represents an objective useful parameter to compare the function of organs in age-matched individuals and evaluate whether heart failure correlates with biological age With this approach, the properties of cardiac stem/progenitor cells can be compared and properly analyzed Therefore, to establish whether biological aging can induce an aging cardiomyopathy independent of other causes, patients have been carefully selected and all known causes of heart failure— hypertension, ischemic heart disease, diabetes, systemic disorders, drug or alcohol abuse and myocarditis—have been excluded (Chimenti et al, 2003) However, the definition of an aging myopathy is further complicated by the necessity to distinguish the senescent failing heart from idiopathic dilated cardiomyopathy