Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling

Paradis, Pierre; Dali‐Youcef, Nassim; Paradis, F. W.; Thibault, Gaétan; Nemer, Mona

doi:10.1073/pnas.97.2.931

Cited by 344 publications

(259 citation statements)

References 47 publications

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“…For example, we did not observe the ventricular hypertrophy or fibrosis, as reported by Paradis et al 15 in cardiac overexpression of the AT 1 receptor (by more than 200-fold). Here, cardiac dilatation and heart failure may reflect abnormal intracellular signaling as a function of the massive increase of these receptors.…”

Section: Discussionsupporting

confidence: 58%

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

232

191

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To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the ␣-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death. The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight amino acid peptide angiotensin II, the effector molecule of the RAS. 1 ACE is a zinc metallopeptidase located on the cell surface of endothelium. In this location, ACE produces angiotensin II adjacent to vascular smooth muscle, a critical target organ for this vasoconstrictor. ACE is also produced by a variety of other tissues including renal tubular epithelium, activated macrophages, proximal gut epithelium, and areas of the brain. Endothelium and these other tissues make the isozyme of ACE, termed somatic ACE, which consists of two catalytic domains that are independently capable of producing angiotensin II. Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease. 5 Genetic studies reported a link between somatic ACE polymorphisms and the incidence of cardiac hypertrophy, sudden cardiac death, and acute coronary events. 6 This is consistent with the clinical effectiveness of ACE inhibitors in treating heart failure. 7 The beneficial effects of ACE inhibitors may not be solely the result of blood pressure reduction since other antihypertensive drugs do not produce the same effect. Rather, ACE may directly influence heart function through the local production of angiotensin II. Studies have found that angiotensinogen, renin, and ACE exist in the heart, implying that local generation of angiotensin II

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Section: Discussionsupporting

confidence: 58%

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

232

191

View full text Add to dashboard Cite

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“…AII-induced cardiac hypertrophy results in upregulation of the ANF gene (55). However, since activation of ANF transcription is a hallmark for the genetic changes that accompany cardiac hypertrophy irrespective of etiology, we first tested whether ANF is a direct target for AII.…”

Section: Resultsmentioning

confidence: 99%

“…Total RNA was prepared using TRIZOL reagent (Invitrogen Canada, Inc., Burlington, ON, Canada). Northern blots were performed as previously described (55). QPCR was performed on cDNAs obtained by reverse transcription of 2 g of total RNA using Omniscript reverse transcriptase (QIAGEN, Inc., Mississauga, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…At the level of the heart, AT1R activation causes myocyte hypertrophy and apoptosis (55) and is associated with upregulation of c-jun, c-fos, and the cardiac-specific atrial natriuretic factor (ANF) gene, which is induced during hypertrophy (55,74) AII also activates several STAT family members which have themselves been implicated in cardioprotection, apoptosis, and hypertrophy through mechanisms and effectors that remain to be elucidated (reviewed in reference 9). Similarly, the various signaling pathways activated by AII have all been implicated in cardiac hypertrophy, apoptosis, or both (1,24,46).…”

mentioning

confidence: 99%

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Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

Wang

Paradis

Aries

et al. 2005

Molecular and Cellular Biology

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Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this process; however, which of these directly link receptor activation to transcriptional regulation remains undefined. We used the atrial natriuretic factor (ANF) gene (NPPA) as a marker to elucidate the signaling cascades involved in AII transcriptional responses. We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy. This response maps to STAT and GATA binding sites, and the two elements transcriptionally cooperate to mediate signaling through the JAK-STAT and protein kinase C (PKC)-GATA-4 pathways. PKC phosphorylation enhances GATA-4 DNA binding activity, and STAT-1 functionally and physically interacts with GATA-4 to synergistically activate AII and other growth factor-inducible promoters. Moreover, GATA factors are able to recruit STAT proteins to target promoters via GATA binding sites, which are sufficient to support synergy. Thus, STAT proteins can act as growth factor-inducible coactivators of tissue-specific transcription factors. Interactions between STAT and GATA proteins may provide a general paradigm for understanding cell specificity of cytokine and growth factor signaling.

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“…26,27 In addition to the circulating hormone system, local tissue bound RAAS has also been recognised and well described to modulate cardiac hypertrophy and remodelling. 28 Hyperglycaemia, by causing glycosylation of p53, can also affect the transcription of angiotensinogen and subsequent production of angiotensin II from local RAAS. 29 Of note, there is clinical evidence that RAAS blockade reduces thrombotic complications associated with DM.…”

mentioning

confidence: 99%

Antihypertensive therapy in diabetes mellitus: insights from ALLHAT and the Blood Pressure-Lowering Treatment Trialists’ Collaboration meta-analysis

Varughese

Lip

2005

J Hum Hypertens

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Type 2 diabetes mellitus (DM) is closely associated with hypertension, and the presence of both the conditions results in a high risk for the development of cardiovascular disease (CVD), renal impairment and diabetic retinopathy. Thus, most blood pressure (BP) management guidelines emphasise the importance of concomitant DM as part of overall cardiovascular risk assessment, and the need for more aggressive treatment targets. 1 This approach is all the more important given the huge burden of hypertension on stroke and CVD, and the missed opportunities for prevention. 2 How large is the problem of hypertension in the setting of DM? A recent large cross-sectional survey of over 250 000 patients from general practices across the United Kingdom recently reported that 56.2% of pharmacologically treated and 47.2% of diet-treated patients with DM had hypertension, as compared to 10.3% in those without DM. 3 This was consistent with earlier reports, where the association between DM and hypertension has been demonstrated in up to 65% of patients with DM, having major implications for CVD risk. 4,5 However, what is clear is the greater benefits of appropriate BP treatment on CVD, compared to glycaemic control. For example, in the United Kingdom Prospective Study, a systolic and diastolic BP reduction by 10 mmHg and 5 mmHg respectively has greater CVD risk reduction than lowering glycated haemoglobin by a mean of 0.9%. 6 This was further substantiated by the Hypertension Optimal Treatment Study, suggesting that there should perhaps be no lower threshold beyond which BP lowering is not considered to be beneficial in the setting of DM. 7

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Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling

Cited by 344 publications

References 47 publications

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

Antihypertensive therapy in diabetes mellitus: insights from ALLHAT and the Blood Pressure-Lowering Treatment Trialists’ Collaboration meta-analysis

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