Cellular Basis of Physiological and Pathological Myocardial Growth

Anversa, Piero; Olivetti, G

doi:10.1002/cphy.cp020102

Cited by 36 publications

(55 citation statements)

References 390 publications

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“…In this manner, the number of noninfarcted myocytes provided an anatomical measurement that reflected the degree of cardiac function at euthanasia. 12 The dimension of the infarct was similar in the two groups of mice. Infarct size comprised 56Ϯ5% (total number of LV myocytes in sham-operated control animals, 2.72Ϯ0.30ϫ10 6 ; total number of LV myocytes in infarcted animals, 1.18Ϯ0.13ϫ10 6 ; total number of LV myocytes lost in infarcted animals, 1.54Ϯ0.13ϫ10 6 ) and 54Ϯ6% (total number of LV myocytes in sham-operated control animals, 2.72Ϯ0.30ϫ10 6 ; total number of LV myocytes in infarcted animals, 1.24Ϯ0.15ϫ10 6 ; total number of LV myocytes in sham-operated control animals, 2.72Ϯ0.30ϫ10 6 ; total number of LV myocytes in infarcted animals, 1.18Ϯ0.13ϫ10…”

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confidence: 53%

Regeneration of the Infarcted Heart With Stem Cells Derived by Nuclear Transplantation

Lanza

Moore

Wakayama

et al. 2004

Circulation Research

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Nuclear transfer techniques have been proposed as a strategy for generating an unlimited supply of rejuvenated and histocompatible stem cells for the treatment of cardiac diseases. For this purpose, c-kit-positive fetal liver stem cells obtained from cloned embryos were injected in the border zone of infarcted mice to induce tissue reconstitution. Cloned embryos were derived from somatic cell fusion between nuclei of cultured LacZ-positive fibroblasts and enucleated oocytes of a different mouse strain. We report that regenerating myocardium replaced 38% of the scar at 1 month. The rebuilt tissue expressed LacZ and was composed of myocytes and vessels connected with the coronary circulation. Myocytes were functionally competent and expressed contractile proteins, desmin, connexin43, and N-cadherin. These structural characteristics indicated that the new myocytes were electrically and mechanically coupled. Similarly, the formed coronary arterioles and capillary structures contained blood and contributed, therefore, to tissue oxygenation. Cardiac replacement resulted in an improvement of ventricular hemodynamics and in a reduction of diastolic wall stress. These beneficial effects were obtained by stem cell transdifferentiation and commitment to the cardiac cell lineages. Myocardial growth was independent from fusion of the injected stem cells with preexisting partner cells. In conclusion, c-kit-positive stem cells derived by nuclear transfer cloning restore infarcted myocardium. Although problems currently plague nuclear transplantation, including the potential for epigenetic and imprinting abnormalities, stem cells derived from cloned embryos are sufficiently normal to repair damaged tissue in vivo. Importantly, the magnitude of myocardial regeneration obtained in this study is significantly superior to that achieved with adult bone marrow cells.

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confidence: 53%

Regeneration of the Infarcted Heart With Stem Cells Derived by Nuclear Transplantation

Lanza

Moore

Wakayama

et al. 2004

Circulation Research

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“…However, the selection of patients or hearts to be analyzed has always been based on the chronological age of otherwise healthy individuals. [1][2][3] This understandable approach has neglected several variables of the aging process that cannot be easily quantified but may have a significant impact on organ and/or organism aging. It is a wellestablished fact that chronological age and physical age do not necessarily coincide.…”

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confidence: 99%

“…Aging effects decrease the functional reserve of the heart 1,2 and loss of myocytes 3 contributes to the attenuation of the response of the old heart to sudden changes in ventricular loading. However, the selection of patients or hearts to be analyzed has always been based on the chronological age of otherwise healthy individuals.…”

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confidence: 99%

Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart Failure

Chimenti

Kajstura

Torella

et al. 2003

Circulation Research

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Abstract-Chronological myocardial aging is viewed as the inevitable effect of time on the functional reserve of the heart.Cardiac failure in elderly patients is commonly interpreted as an idiopathic or secondary myopathy superimposed on the old heart independently from the aging process. Thus, aged diseased hearts were studied to determine whether cell regeneration was disproportionate to the accumulation of old dying cells, leading to cardiac decompensation. Endomyocardial biopsies from 19 old patients with a dilated myopathy were compared with specimens from 7 individuals of similar age and normal ventricular function. Ten patients with idiopathic dilated cardiomyopathy were also analyzed to detect differences with aged diseased hearts. Senescent cells were identified by the expression of the cell cycle inhibitor p16 INK4a and cell death by hairpin 1 and 2. Replication of primitive cells and myocytes was assessed by MCM5 labeling, myocyte mitotic index, and telomerase function. Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16INK4a positive primitive cells and myocytes, and no structural damage. Cell death markedly increased and occurred only in cells expressing p16INK4a that had significant telomeric shortening. Cell multiplication, mitotic index and telomerase increased but did not compensate for cell death or prevented telomeric shortening. Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16INK4a labeling. In conclusion, telomere erosion, cellular senescence, and death characterize aged diseased hearts and the development of cardiac failure in humans. Key Words: aging Ⅲ telomeric shortening and telomerase activity Ⅲ p16INK4a marker of cellular senescence Ⅲ cardiac primitive cells Ⅲ heart failure M yocardial aging in humans has been studied extensively and two major conclusions have been reached. Aging effects decrease the functional reserve of the heart 1,2 and loss of myocytes 3 contributes to the attenuation of the response of the old heart to sudden changes in ventricular loading. However, the selection of patients or hearts to be analyzed has always been based on the chronological age of otherwise healthy individuals. [1][2][3] This understandable approach has neglected several variables of the aging process that cannot be easily quantified but may have a significant impact on organ and/or organism aging. It is a wellestablished fact that chronological age and physical age do not necessarily coincide. An 80-year-old man or woman may appear as young as a 60-year-old person. Similarly, organism and organ age do not proceed at the same pace. 4 -6 In general, there is little appreciation of these unpredictable factors and aged patients with cardiac decompensation are diagnosed according to classified diseases, excluding that aging per se can be the etiology of the pathological condition.To establish whether aging alone results in a dilated myopathy with characteristics different from idiopathic dilated cardiomyopathy (...

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“…RVH occurs in response to increased wall stress caused by PH. Because cardiac myocytes in the postnatal animal are largely incapable of proliferation, the increased wall thickness reflects a physical increase in individual myocyte size, resulting from the ordered deposition of additional sarcomeres (3). In this regard, we also noted that chronically hypoxic MEKK2 Ϫ/Ϫ mice exhibited reduced neomuscularization of pulmonary microvessels compared with WT mice, despite an elevation of RV systolic pressure in response to hypoxia.…”

Section: Discussionmentioning

confidence: 56%

MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension

Brown

Ambler

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Brown RD, Ambler SK, Li M, Sullivan TM, Henry LN, Crossno JT Jr, Long CS, Garrington TP, Stenmark KR. MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 304: H269 -H281, 2013. First published November 2, 2012; doi:10.1152/ajpheart.00158.2012.-Pulmonary hypertension (PH) results in pressure overload of the right ventricle (RV) of the heart, initiating pathological RV remodeling and ultimately leading to right heart failure. Substantial research indicates that signaling through the MAPK superfamily mediates pathological cardiac remodeling. These considerations led us to test the hypothesis that the regulatory protein MAPKKK-2 (MEKK2) contributes to RV hypertrophy in hypoxiainduced PH. Transgenic mice with global knockout of MEKK2 (MEKK2 Ϫ/Ϫ mice) and age-matched wild-type (WT) mice were exposed to chronic hypobaric hypoxia (10% O2, 6 wk) and compared with animals under normoxia. Exposure to chronic hypoxia induced PH in WT and MEKK2 Ϫ/Ϫ mice. In response to PH, WT mice showed RV hypertrophy, demonstrated as increased ratio of RV weight to body weight, increased RV wall thickness at diastole, and increased cardiac myocyte size compared with normoxic control animals. In contrast, each of these measures of RV hypertrophy seen in WT mice after chronic hypoxia was attenuated in MEKK2 Ϫ/Ϫ mice. Furthermore, chronic hypoxia elicited altered programs of hypertrophic and inflammatory gene expression consistent with pathological RV remodeling in WT mice; MEKK2 deletion selectively inhibited inflammatory gene expression compared with WT mice. The actions of MEKK2 were mediated in part through regulation of the abundance and phosphorylation of its effector, ERK5. In conclusion, signaling by MEKK2 contributes to RV hypertrophy and altered myocardial inflammatory gene expression in response to hypoxiainduced PH. Therapies targeting MEKK2 may protect the myocardium from hypertrophy and pathological remodeling in human PH. cardiac remodeling; inflammation; myocytes; hypoxia; pulmonary hypertension; mitogen-activated protein kinase kinase kinase-2; ERK5

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Cellular Basis of Physiological and Pathological Myocardial Growth

Cited by 36 publications

References 390 publications

Regeneration of the Infarcted Heart With Stem Cells Derived by Nuclear Transplantation

Regeneration of the Infarcted Heart With Stem Cells Derived by Nuclear Transplantation

Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart Failure

MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension

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