Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart

Lakó-Futó, Zoltán; Szokodi, István; Sármán, Balázs; Földes, Gábor; Tokola, Heikki; Ilves, Mika; Leskinen, Hanna; Vuolteenaho, Olli; Skoumal, Réka; deChâtel, Rudolf; Ruskoaho, Heikki; Tóth, Miklós

doi:10.1161/01.cir.0000093193.63314.d9

Cited by 40 publications

(32 citation statements)

References 48 publications

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“…Lamp2 has been shown to cause cardiac hypertrophy associated with glycogen accumulation (1,30,33). Agtr2 has been implicated in cardiac hypertrophic process (9,18). No mutation was found in either Lamp2 or Agtr2 coding sequences.…”

Section: Resultsmentioning

confidence: 97%

A novel mouse model of X-linked cardiac hypertrophy

Leatherbury

Yu²,

Chatterjee³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Lo CW. A novel mouse model of X-linked cardiac hypertrophy. Am J Physiol Heart Circ Physiol 294: H2701-H2711, 2008. First published April 18, 2008 doi:10.1152/ajpheart.00160.2007.-We recovered a novel mouse mutant exhibiting neonatal lethality associated with severe fetal cardiac hypertrophy and with some adult mice dying suddenly with left ventricular hypertrophic cardiomyopathy. Using Doppler echocardiography, we screened surviving adult mice in this mutant line for cardiac hypertrophy. Cardiac dimensions were obtained either from two-dimensional images collected using a novel ECG-gated ultra-high-frequency ultrasound system or by traditional M-mode imaging on a clinical ultrasound system. These analyses identified, among the littermates, two populations of mice: those with apparent cardiac hypertrophy with hypercontractile function characterized by ejection fraction of 75-80%, and normal littermates with ejection fraction of 53-55%. Analysis of the ECG-gated two-dimensional cines indicated that the hypertrophy was of the nonobstructive type. Further analysis of heart-to-body weight ratio confirmed the ultrasound diagnosis of left ventricular hypertrophic cardiomyopathy. Histopathology showed increased ventricular wall thickness, enlarged myocyte size, and mild myofiber disarray. Ultrastructural analysis by electron microscopy revealed mitochondria hyperproliferation and dilated sarcoplasmic reticulum. Genome scanning using microsatellite DNA markers mapped the mutation to the X chromosome. DNA sequencing showed no mutations in the coding regions of several candidate genes on the X chromosome, including several known to be associated with left ventricular hypertrophic cardiomyopathy. These findings suggest that this mouse line may harbor a mutation in a novel gene causing X-linked cardiomyopathy.echocardiography; X-linked cardiomyopathy; hypertrophic cardiomyopathy; ultrasound HYPERTROPHIC CARDIOMYOPATHY (HCM) is a major cardiovascular disease in human adults and children (17,22), with a prevalence of 1:500 in the young and likely higher in older individuals due to age-dependent penetrance (23). It has varied presentations, from no symptoms to severe heart failure or sudden cardiac death, that do not correlate directly with the anatomic abnormality. It is a major cause of sudden cardiac death in apparently healthy, young individuals (24). Infants that present with cardiac hypertrophy may present with a murmur, but some also have severe congestive heart failure and a high mortality (38,42). In children and adults, HCM may also be a major cause of morbidity and mortality (25,28,32).HCM is characterized by thickening of the ventricular heart muscle peculiar to the ventricular myocardium and not secondary to another defect, such as aortic valve disease or systemic hypertension. There are clinical subcategories, with 25% of human adults having hypertrophic obstructive cardiomyopathy with asymmetric hypertrophy of the interventricular septum. This is usually associated with obstructive flow from the left ventricula...

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Section: Resultsmentioning

confidence: 97%

A novel mouse model of X-linked cardiac hypertrophy

Leatherbury

Yu²,

Chatterjee³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…25 However, intact AT 2 receptors are also important for hypertrophy of cardiac cells. 26 Ang II-treated cells are arrested in the G 1 -phase and do not progress into the S-phase. 25,27 Mitogens such as epidermal growth factor and Ang II induce early immediate genes and Hox genes in proximal tubular cells.…”

Section: Ang II and Hypertrophymentioning

confidence: 99%

Angiotensin II and Cell Cycle Regulation

Wolf

Wenzel

2004

Hypertension

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Abstract-Angiotensin II has emerged as an important growth factor for vascular, cardiac, and renal cells. Depending on the specific cell type and presence of other growth factors, angiotensin II induces proliferation (replication of DNA with subsequent successful division of cells), hypertrophy (increase in cell size, cell protein, and mRNA content without DNA replication), apoptosis (programmed cell death), or differentiation. Such angiotensin II-mediated modulation of growth process may underlie various pathophysiological processes such as atherosclerosis, vascular and cardiac remodeling, and progression of chronic renal disease. Clearly, angiotensin II-induced proliferation requires complete cell progression through the various steps of the cell cycle. In contrast, cells undergoing angiotensin II-mediated hypertrophy are arrested in the G 1 -phase. Upregulation of cell cycle-dependent kinase inhibitors (eg, p27 Kip1 ) plays an important role in this process. Although accumulating evidence suggests that apoptosis is cell cycle-dependent, only few data are currently available concerning the interaction of angiotensin II with the cell cycle machinery in apoptosis. We review the various angiotensin II-mediated growth processes and their relationship to events governing cell cycle regulation.

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“…Other factors can be related to the genetic background of the individual (modifier genes); the role of modifier genes has been supported by experimental studies in transgenic mice and also in human beings, in whom several genetic polymorphisms mainly related to the renin-angiotensin-aldosterone system have been shown to play a role. The most commonly implicated is the insertion/ deletion polymorphism of the angiotensin-converting enzyme, which has been shown to be associated with the risk of sudden cardiac death and the severity of LVH (52-57), but endothelin (54) and angiotensin II type 2 receptor (58) polymorphisms have also been reported as modifier genes. However, the intrinsic variability related to causal genes makes the search for modifier genes complicated.…”

Section: Causal Genes and Mutationsmentioning

confidence: 99%

The Genetic Bases of Cardiomyopathies

Richard

Villard

Charron

et al. 2006

Journal of the American College of Cardiology

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Cardiomyopathies represent an important cause of cardiovascular morbidity and mortality due to heart failure, arrhythmias, and sudden death. A majority of hypertrophic cardiomyopathies (HCM) and at least 30% of dilated cardiomyopathies (DCM) are familial forms, with most often an autosomal dominant mode of inheritance. Over the last 15 years, our knowledge on the genetic bases of these diseases has considerably improved. Cardiomyopathies are characterized by a great genetic heterogeneity at both allelic and non-allelic levels. Hypertrophic cardiomyopathies are mainly linked to mutations on genes encoding sarcomeric proteins, and beta myosin heavy chain and myosin binding protein C gene mutations account for about 80% of genotyped cases. Familial DCM is associated with mutations in genes encoding sarcomeric proteins but also other proteins of the myocyte, such as cytoskeletal or nuclear membrane proteins. Due to the genetic heterogeneity and the variable clinical expressivity of these diseases, the relations between genotype and phenotype remain complex, but the age of onset, the clinical severity, or associated phenotypes may be, at least in part, related to the precise gene mutations. Therefore, besides a better understanding of the molecular basis for cardiac remodeling and heart failure, the genetic analysis of cardiomyopathies is going to play an increasing role in the routine management of these patients in the following years, particularly in HCM. (J Am Coll Cardiol 2006;48:A79 -89)

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Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart

Cited by 40 publications

References 48 publications

A novel mouse model of X-linked cardiac hypertrophy

A novel mouse model of X-linked cardiac hypertrophy

Angiotensin II and Cell Cycle Regulation

The Genetic Bases of Cardiomyopathies

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