http://files.fisiologiaucs.webnode.com/200000046-0c34d0d2eb/Molecular%20distinction%20between%20physiological%20and%20pathological%20cardiac%20hypertrophy.pdf

Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies.

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Mechanisms of physiological and pathological cardiac hypertrophy

Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle soon after birth in mammals Although the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and species-specific differences may exist, it appears that for the vast majority of adult cardiac myocytes the predominant form of growth postnatally is an increase in cell size (hypertrophy) not number Unfortunately, this limits the ability of the heart to restore function after any significant injury Interest in novel regenerative therapies has led to the accumulation of much information on the mechanisms that regulate the rapid proliferation of cardiac myocytes in utero, their cell cycle exit in the perinatal period, and the permanent arrest (terminal differentiation) in adult myocytes The recent identification of cardiac progenitor cells capable of giving rise to cardiac myocyte-like cells has challenged the dogma that the heart is a terminally differentiated organ and opened new prospects for cardiac regeneration In this review, we summarize the current understanding of cardiomyocyte cell cycle control in normal development and disease In addition, we also discuss the potential usefulness of cardiomyocyte self-renewal as well as feasibility of therapeutic manipulation of the cardiac myocyte cell cycle for cardiac regeneration

https://www.physiology.org/doi/pdf/10.1152/physrev.00032.2006

Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

FoxO transcription factors promote autophagy in cardiomyocytes.

Down syndrome is caused by a genomic imbalance of human chromosome 21 which is mainly observed as trisomy 21. The regions on human chromosome 21 are syntenically conserved in three regions on mouse chromosomes 10, 16 and 17. Ts65Dn mice, the most widely used model for Down syndrome, are trisomic for approximately 56.5% of the human chromosome 21 syntenic region on mouse chromosome 16. To generate a more complete trisomic mouse model of Down syndrome, we have established a 22.9 Mb duplication spanning the entire human chromosome 21 syntenic region on mouse chromosome 16 in mice using Cre/loxP-mediated long-range chromosome engineering. The presence of the intact duplication in mice was confirmed by fluorescent in situ hybridization and BAC-based array comparative genomic hybridization. The expression levels of the genes within the duplication interval reflect gene-dosage effects in the mutant mice. The cardiovascular and gastrointestinal phenotypes of the mouse model were similar to those of patients with Down syndrome. This new mouse model represents a powerful tool to further understand the molecular and cellular mechanisms of Down syndrome.

Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities

The serine/threonine kinase Akt regulates cellular survival, proliferation, gene transcription, protein translation, metabolism, and differentiation. Although Akt substrates are found throughout the cell, activated Akt normally accumulates in the nucleus, suggesting that biologically relevant targets are located there. Consequences of nuclear Akt signaling in cardiomyocytes were explored by using nuclear-targeted Akt (Akt-nuc). Accumulation of Akt-nuc did not provoke hypertrophy, unlike constitutively activated Akt. Instead, Akt-nuc inhibited hypertrophy concurrent with increased atrial natriuretic peptide (ANP) expression that depended upon phosphatidylinositol-3 kinase activity. Akt-nuc antihypertrophic effects were blocked by inhibition of either guanylyl cyclase A receptor or cyclic guanosine monophosphate-dependent protein kinase in cultured cardiomyocytes. Corroborating evidence showed blunted acute hypertrophic remodeling in Akt-nuc transgenic mice after transverse aortic constriction coincident with higher ANP expression and smaller myocyte volume. In addition, Akt-nuc expression improved systolic function and survival in the chronic phase of transverse aortic constriction-induced hypertrophy. Thus, Akt-nuc antagonizes certain aspects of hypertrophy through autocrine/paracrine stimulation of a phosphatidylinositol-3 kinase-dependent signaling cascade that promotes ANP expression, resulting in a unique combination of prosurvival coupled with antihypertrophic signaling.

https://www.pnas.org/content/pnas/103/32/11946.full.pdf

Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy

Using a confocal laser scanning microscope (CLSM), we observed subcellular three-dimensional (3-D) arrangements of actin filaments stained with fluorescein-labeled phalloidin during myofibrinogenesis of chick embryonic heart (7- to 13-somite stages). Serial optical tomograms were obtained from whole-mounted heart tubes and reconstructed into stereoscopic images. Development of myofibrils in myocardial differentiation considerably differed in inner and outer myocardial cell layers. In the outer layer, initial myofibrils appeared along cell membranes at the 8-somite stage. They increased rapidly and constituted network structures with spatial extension over cell-cell junctions. In the inner layer, myofibrils appeared at the bottom, facing the cardiac jelly, at the 10-somite stage, and, when the straight heart tube began to bend, they were already aligned circumferentially in the direction of the heart tube. Double staining of fluorescein-phalloidin and DiI [1,1'-dioctadecyl-3,3,3',3'-tetramethylindo-carbocyanine perchlorate; DiI-C18-(3)] of the looped heart revealed that while myocytes in the outer layer were round, those of the inner layer were spindle-shaped, and their long axes coincided with the circumferential direction. These results suggest that the circumferentially arranged myofibrils at the bottom of the inner layer may play an important role in the looping of the heart tube.

3-D observation of actin filaments during cardiac myofibrinogenesis in chick embryo using a confocal laser scanning microscope.

Background There are few studies of the therapeutic regimens for the prevention of stenotic transformation of aneurysms in Kawasaki disease (KD). The aim of this study was to assess the prophylactic effect of combined therapy in the acute stage and convalescent- to chronic-stage against the formation of stenotic lesions. Methods and Results In 85 patients, 103 giant aneurysms (ANl), 46 medium-sized aneurysms (ANm), and 13 small aneurysms (ANs) were analyzed. With respect to therapy in the acute stage, no localized stenosis of ANl in the left coronary artery was noted in patients who received high-dose gamma globulin therapy (G). For ANm, the group (G) showed a significantly higher regression rate than the aspirin group and steroids group. Furthermore, no coronary artery occlusion/recanalization of ANl occurred with the prophylactic regimen of aspirin and warfarin {aw}. Prophylaxis {aw} and the prophylactic regimen of aspirin alone {a} significantly lowered the incidence compared with either the prophylactic regimen of warfarin {w} or no prophylaxis {n}. However, no significant differences were noted between prophylaxis {w} and {n}. Conclusions High-dose gamma globulin therapy in the acute stage of KD is the first choice for the prevention of stenotic transformation. Prophylaxis {aw} is recommended for ANl. (Circ J 2005; 69: 265 - 272)

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Isao Shiraishi

Papers

Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities

Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy

3-D observation of actin filaments during cardiac myofibrinogenesis in chick embryo using a confocal laser scanning microscope.

Long-term changes in coronary artery aneurysms in patients with Kawasaki disease: comparison of therapeutic regimens.

Intrapartum fetal heart rate monitoring in cases of congenital heart disease.