Cardiac hypertrophy and fibrosis in chronic l-NAME-treated AT2 receptor-deficient mice

Groß, Volkmar; Obst, Michael; Kiss, Éva; Janke, Jürgen; Mazák, István; Shagdarsuren, Erdenechimeg; Müller, Dominik N.; Langenickel, Thomas; Gröne, Hermann Josef; Luft, Friedrich C.

doi:10.1097/00004872-200405000-00023

Cited by 20 publications

(24 citation statements)

References 47 publications

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“…To further document cardiac hypertrophy, we performed morphometric analyses by counting the number of cardiomyocyte nuclei per surface of heart section and by measuring cardiomyocyte cross-sectional areas. 19,20 The 2 quantifications confirmed that Ang II infusion induced a stronger hypertrophy in WT mice than in CalpTG mice (Figure 4b and 4c).…”

Section: Ang Ii-dependent Cardiovascular Hypertrophy In Wt and Calptgsupporting

confidence: 54%

Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension

Letavernier

Perez

Bellocq

et al. 2008

Circulation Research

146

139

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Abstract-In hypertension, angiotensin (Ang) II is a critical mediator of cardiovascular remodeling, whose prominent features include myocardial and vascular media hypertrophy, perivascular inflammation, and fibrosis. The signaling pathways responsible for these alterations are not completely understood. Here, we investigated the importance of calpains, calcium-dependent cysteine proteases. We generated transgenic mice constitutively expressing high levels of calpastatin, a calpain-specific inhibitor. Chronic infusion of Ang II led to similar increases in systolic blood pressure in wild-type and transgenic mice. In contrast, compared with wild-type mice, transgenic mice displayed a marked blunting of Ang II-induced hypertrophy of left ventricle. Ang II-dependent vascular remodeling, ie, media hypertrophy and perivascular inflammation and fibrosis, was also limited in both large arteries (aorta) and small kidney arteries from transgenic mice as compared with wild type. In vitro experiments using vascular smooth muscle cells showed that calpastatin transgene expression blunted calpain activation by Ang II through epidermal growth factor receptor transactivation. In vivo and in vitro models of inflammation showed that impaired recruitment of mononuclear cells in transgenic mice was attributable to a decrease in both the release of and the chemotactic response to monocyte chemoattractant protein-1. Finally, results from collagen synthesis assay and zymography suggested that limited fibrogenesis was attributable to a decrease in collagen deposition rather than an increase in collagen degradation.

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Section: Ang Ii-dependent Cardiovascular Hypertrophy In Wt and Calptgsupporting

confidence: 54%

Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension

Letavernier

Perez

Bellocq

et al. 2008

Circulation Research

146

139

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“…Cardiac fibrosis is one of the classic features of hypertrophy and is characterized by the expansion of the extracellular matrix attributed to the accumulation of collagen, especially collagen I and connective tissue growth factor. 20,21 It is important to understand the mechanism that stimulates collagen deposition in the heart and to identify approaches to block these processes. One of the findings of this study revealed that Lmcd1 augments cardiac fibrosis and promotes expression of several fibrotic mediators mediated by pressure overload.…”

Section: Bian Et Al Lmcd1 Mediates Cardiac Hypertrophy 261mentioning

confidence: 99%

“…22,23 Calcineurin dephosphorylates NFATs in response to increased intracellular calcium and regulates gene expression in a variety of calcium-sensitive tissues, such as brain, muscle, and lymphocytes. 21,22 Transcriptional activity of NFATs depends on dephosphorylation by calcineurin, which leads to nuclear translocation. [23][24][25] Recent studies revealed that muscle LIM protein directly associates with calcineurin, and this interaction is critical for calcineurin-NFAT signaling.…”

Section: Bian Et Al Lmcd1 Mediates Cardiac Hypertrophy 261mentioning

confidence: 99%

LIM and Cysteine-Rich Domains 1 Regulates Cardiac Hypertrophy by Targeting Calcineurin/Nuclear Factor of Activated T Cells Signaling

et al. 2010

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Abstract-LIM domain proteins are important regulators in cell growth, cell fate determination, cell differentiation, and remodeling of the cell cytoskeleton. LIM and cysteine-rich domains 1 (Lmcd1) is a novel protein that contain 2 LIM domains with regular spacing in the carboxy-terminal region. However, its roles in cardiac growth remain unknown. Here, we investigated whether Lmcd1 regulates cardiac hypertrophy in vitro and in vivo and elucidated the underlying molecular mechanisms. We used primary cultured cardiac myocytes and cardiac-specific Lmcd1 transgenic mice. In wild-type mice subjected to the aortic banding, cardiac hypertrophy was evident at 8 weeks. In transgenic mice, however, cardiac hypertrophy was significantly greater than that in wild-type mice, as estimated by heart weight:body weight ratio, cardiomyocyte area, and echocardiographic measurements, as well as cardiac atrial natriuretic peptide and B-type natriuretic peptide mRNA and protein levels. Our results further showed that cardiac fibrosis observed in wild-type aortic banding mice was augmented in transgenic aortic banding mice. Importantly, calcineurin activity and nuclear factor of activated T cells activation level were increased more in transgenic mice than those in wild-type mice after 8-week aortic banding. In vitro experiments in cardiac myocytes further revealed that angiotensin II-induced calcineurin activity and nuclear factor of activated T cells activation were enhanced by overexpression but blunted by downregulation of Lmcd1. In conclusion, our results suggest that Lmcd1 plays a critical role in the development of cardiac hypertrophy via activation of calcineurin/nuclear factor of activated T cells signaling pathway. Key Words: cardiac hypertrophy Ⅲ fibrosis Ⅲ Lmcd1 Ⅲ calcineurin Ⅲ NFAT C ardiac hypertrophy is a response of the myocardium to increased workload, characterized by an increase of myocardial mass and accumulation of extracellular matrix, leading to left ventricular (LV) dilatation, fibrosis, and impaired systolic function, and it potentates the development of ventricular arrhythmias, heart failure, and subsequent cardiovascular mortality. 1,2 Although initially a beneficial adaptive response, prolonged hypertrophy may result in ventricular dilatation and heart failure, which is increasing in prevalence and is a debilitating disease with high rates of mortality and morbidity. [3][4][5][6] However, antihypertensive therapies and aortic valve replacement are the only 2 treatments proven to effectively reverse both structural and functional cardiac abnormalities associated with pathological cardiac hypertrophy. Understanding the underlying processes regulating cardiac remodeling will allow us to identify specific new therapies to improve the long-term outcomes of pathological cardiac hypertrophy in patients.LIM domain proteins are well recognized as key components of the regulatory machinery of the cell and are important regulators in cell growth, cell fate determination, cell differentiation, and remodeling of the ce...

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“…Briefly, a telemetry probe catheter (TA11-PA40; Data Sciences International) was inserted into the surgically exposed carotid artery. 23 After surgery, all mice were allowed at least 7 days to recover. Before Ang II/L-NAME treatment, baseline values were continuously recorded for 3 days and averaged.…”

Section: Telemetric Mean Arterial Pressure Measurementsmentioning

confidence: 99%

Vascular Endothelial Cell–Specific NF-κB Suppression Attenuates Hypertension-Induced Renal Damage

Henke

Schmidt‐Ullrich

Dechend

et al. 2007

Circulation Research

Self Cite

127

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Abstract-Nuclear factor kappa B (NF-B) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-B suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-B super-repressor IB␣⌬N (Tie-1-⌬N mice) overexpression. We confirmed cell-specific IB␣⌬N expression and reduced NF-B activity after TNF-␣ stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-Larginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-⌬N and control mice. In contrast to control mice, Tie-1-⌬N mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-B targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-B activation and hypertension-induced renal damage. We conclude that in vivo NF-B suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure. Key Words: hypertension Ⅲ endothelium Ⅲ NF-B Ⅲ target-organ damage H ypertension is a risk factor for target-organ damage such as cardiac and renal disease. 1 Endothelial cell injury initiates adhesion molecule and chemokine expression promoting inflammation that contributes to the pathogenesis of hypertension-induced target organ damage. [2][3][4][5] Patients with severe hypertension and target-organ damage often show elevated angiotensin (Ang) II levels and reduced nitric oxide (NO) production. Ang II signaling blockade reduces blood pressure and blunts the development and progression of vascular disease in small and large vessels in experimental animal models and in humans. Ang II also elicits an inflammatory response in both endothelial cells 6 and vascular smooth muscle cells. 7,8 Numerous in vitro and in vivo studies demonstrated that Ang II activates the nuclear factor kappa B (NF-B), a major transcription factor in mediating inflammation and innate immunity. 4,6 -8 In resting cells, NF-B resides inactive in the cytoplasm by forming complexes with the inhibitor of B (I〉) proteins. Exposure to extracellular stimuli like TNF-␣, IL-1, reactive oxygen species, Ang II, and numerous other activators leads to rapid phosphorylation, site-specific ubiquitination, and subsequent degradation of the IB proteins by the 26S proteasome. 9 The resulting free NF-B molecules translocate to the nucleus and regulate target gene expression. The targets include genes involved in the control of cell proliferation, apoptosis, innate, and adaptive immune response. 10,11 NF-B and inflammation play an important role in the development of the target organ damage. 4,[12][13][14][15][16][17] However, inhibition of NF-B signaling could also be detrimental. 18,19 Furthermore, the ideal site for NF-B inhibition in the vesse...

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Cardiac hypertrophy and fibrosis in chronic l-NAME-treated AT2 receptor-deficient mice

Abstract: The AT2 receptor is not essential for development of L-NAME-induced cardiac hypertrophy, fibrosis and concomitant changes in left ventricular performance. In contrast, the AT2 receptor offers a protective effect.

Cited by 20 publications

References 47 publications

Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension

Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension

LIM and Cysteine-Rich Domains 1 Regulates Cardiac Hypertrophy by Targeting Calcineurin/Nuclear Factor of Activated T Cells Signaling

Vascular Endothelial Cell–Specific NF-κB Suppression Attenuates Hypertension-Induced Renal Damage

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