Regulatory T Cells Ameliorate Angiotensin II–Induced Cardiac Damage

Kvakan, Heda; Kleinewietfeld, Markus; Qadri, Fatimunnisa; Park, Joon-Keun; Fischer, Robert; Schwarz, Ines; Rahn, Hans-Peter; Plehm, Ralph; Wellner, Maren; Elitok, Saban; Gratze, Petra; Dechend, Ralf; Luft, Friedrich C.; Müller, Dominik N.

doi:10.1161/circulationaha.108.832782

Cited by 296 publications

(228 citation statements)

References 51 publications

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“…In contrast, proteins involved in actin-filament organization, lymphocyte activation (including T-cell activation), and cell projection organization (including neuron projection development and axonogenesis) were enriched in hypertrophic but not acutely stressed hearts (Table I). This finding is consistent with T-cell infiltration and sympathetic nerve generation being increased in hypertrophic hearts (38,39). Our analyses showed that different cellular pathways were activated in cardiac myocytes in response to acute or chronic pressure overload.…”

Section: Quantification Of Dynamic Phosphoproteomic Profiles Respondisupporting

confidence: 91%

Quantitative Phosphoproteomic Study of Pressure-Overloaded Mouse Heart Reveals Dynamin-Related Protein 1 as a Modulator of Cardiac Hypertrophy

Chang

Wang

et al. 2013

Molecular & Cellular Proteomics

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Pressure-overload stress to the heart causes pathological cardiac hypertrophy, which increases the risk of cardiac morbidity and mortality. However, the detailed signaling pathways induced by pressure overload remain unclear. Here we used phosphoproteomics to delineate signaling pathways in the myocardium responding to acute pressure overload and chronic hypertrophy in mice. Myocardial samples at 4 time points (10, 30, 60 min and 2 weeks) after transverse aortic banding (TAB) in mice underwent quantitative phosphoproteomics assay. Temporal phosphoproteomics profiles showed 360 phosphorylation sites with significant regulation after TAB. Multiple mechanical stress sensors were activated after acute pressure overload. Gene ontology analysis revealed differential phosphorylation between hearts with acute pressure overload and chronic hypertrophy. Most interestingly, analysis of the cardiac hypertrophy pathway revealed phosphorylation of the mitochondrial fission protein dynamin-related protein 1 (DRP1) by prohypertrophic kinases. Phosphorylation of DRP1 S622 was confirmed in TAB-treated mouse hearts and phenylephrine (PE)-treated rat neonatal cardiomyocytes. TAB-treated mouse hearts showed phosphorylation-mediated mitochondrial translocation of DRP1. Inhibition of DRP1 with the small-molecule inhibitor mdivi-1 reduced the TAB-induced hypertrophic responses. Mdivi-1 also prevented PE-induced hypertrophic growth and oxygen consumption in rat neonatal cardiomyocytes. We reveal the signaling responses of the heart to pressure stress in vivo and in vitro. Hypertension or acute aortic stenosis causes pressure overload in the left ventricle (LV) 1 , and prolonged pressure overload leads to pathological cardiac hypertrophy. Although beneficial initially, hypertrophy in the heart signals metabolic, structural and functional abnormalities and might lead to abnormal cardiac function (1). Patients with LV hypertrophy have increased risk of heart failure, arrhythmia and death (2, 3). Therefore, inhibition of the hypertrophic heart is proposed as a therapeutic target (1, 4). However, one of the major challenges but also the prerequisite to preventing cardiac hypertrophy is a comprehensive understanding of the mechanism to precisely prevent pathologic cardiac growth without affecting homeostasis (1).The signaling pathways leading to cardiac hypertrophy with chronic pressure overload have been extensively studied by genetic and pharmacological means (1). Proteomic and transcriptomic approaches have been used to study global changes in protein and mRNA expression in hypertrophic hearts (5-7). Acute pressure overload of the heart leads to altered myocardial energy metabolism (8 -10) and contractile function (9,11,12). However, the signaling pathways contributing to early changes in cardiomyocytes remain unclear.Protein phosphorylation allows cells to quickly respond to stimuli and transmit signals by regulating enzymatic activity, protein subcellular localization, protein interaction partners, and protein stability (13). Protein pho...

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Section: Quantification Of Dynamic Phosphoproteomic Profiles Respondisupporting

confidence: 91%

Quantitative Phosphoproteomic Study of Pressure-Overloaded Mouse Heart Reveals Dynamin-Related Protein 1 as a Modulator of Cardiac Hypertrophy

Chang

Wang

et al. 2013

Molecular & Cellular Proteomics

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“…8,9,15 Both the innate and the adaptive immune responses have been implicated in cardiovascular disease, particularly in hypertensive renal pathology 16 and, more recently, in vascular and heart disease. 12,[17][18][19] Indeed, it was previously showed that the innate immune system is involved in Ang II and DOCA/salt-induced hypertension and vascular injury and in aldosterone-induced vascular damage in a blood pressure-independent fashion. [11][12][13] Other investigators have as well more recently confirmed a Figure 1.…”

Section: Discussionmentioning

confidence: 99%

Reduced Macrophage-Dependent Inflammation Improves Endothelin-1–Induced Vascular Injury

Javeshghani

Barhoumi²,

Idris-Khodja³

et al. 2013

Hypertension

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E ndothelin-1 (ET)-1, a 21-aa peptide produced by endothelial and other cells, is one of the most potent vasoconstrictors.1,2 Plasma ET-1 is increased in patients with essential hypertension and in hypertension associated with systemic disorders, in atherosclerosis and heart failure, as well as in other cardiovascular and metabolic disorders, and in chronic kidney disease.3 ET-1 plays a role in the development of hypertension by causing vascular damage and inflammation. 4,5 Transgenic mice overexpressing ET-1 specifically in endothelial cells (eET-1) present endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. 6,7 The immune system plays a role in hypertension and vascular injury. [8][9][10] The innate immune system is involved in angiotensin (Ang) II, deoxycorticosterone acetate (DOCA)/ salt, and aldosterone-induced hypertension and vascular damage. [11][12][13] Ang II, DOCA/salt, and aldosterone infusion caused an increase in vascular monocyte/macrophage infiltration. Ang II and DOCA/salt-induced hypertension and vascular remodeling, oxidative stress, and inflammation were blunted in a model with reduced monocytes/ macrophages, the osteopetrotic (Op) mouse, which is deficient in macrophage colony stimulating factor (CSF) 11,12 because of a thymidine (T) insertion in the coding region of the colony stimulating factor (Csf1) gene that generates a stop codon 21 bp downstream.14 Similarly, aldosterone-induced endothelial dysfunction and vascular oxidative stress were decreased in Csf1Op/+ mice. 13 The innate immune system could play a role in ET-1-induced vascular injury, because the inflammation observed in eET-1 is characterized by an increase in vascular monocyte/macrophage infiltration. However, this remains to be demonstrated.To test the hypothesis that innate immunity participates in ET-1-induced vascular injury, we studied whether vascular injury induced by increased expression of ET-1 is prevented in eET-1 mice crossed with Csf1Op/+ mice that have reduced monocyte/macrophage-dependent inflammation.Abstract-Transgenic mice with endothelium-specific endothelin-1 (ET-1) overexpression exhibit endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. We previously observed that monocytes/macrophages play a role in angiotensin II, aldosterone, and deoxycorticosterone acetate/salt-induced vascular remodeling, oxidative stress, and inflammation using a model with reduced monocytes/macrophages, the osteopetrotic (Op) mouse, which has a mutation in the macrophage colony stimulating factor (Csf1) gene. However, it is unknown whether monocytes/ macrophages are implicated in adverse vascular effects of ET-1. We hypothesized that reduction in monocytes/ macrophages would blunt ET-1-induced vascular injury. We performed a study on 4-to 6-month-old male mice with endothelium-specific ET-1 overexpression (eET-1), reduction in CSF1 (Csf1Op/+ ), or both (eET-1/Csf1Op/+ ), and their wildtype littermate control mice. There was no difference in systolic blood pre...

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“…13) Matsumoto, et al also reported that transfer of Tregs attenuated myocardial infarction-induced ventricular remodelling in mice. 14) These fi ndings suggest that peripheral circulating Tregs might be involved in the pathogenesis of left ventricular dysfunction during development of heart failure.…”

Section: Cd4mentioning

confidence: 97%

Prognostic Value of Circulating Regulatory T Cells for Worsening Heart Failure in Heart Failure Patients With Reduced Ejection Fraction

et al. 2014

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SummaryRegulatory T cells (Tregs) play a crucial role in the negative regulation of immune responses. Recent studies suggest that Tregs are involved in the pathogenesis of atherosclerosis and myocarditis. Here, we investigated the involvement of Tregs on worsening heart failure (HF) in patients with reduced ejection fraction (HF-REF). The study population consisted of 32 HF-REF patients who were hospitalized for worsening HF, and 18 control subjects. Cardiac function was evaluated by echocardiography. A single venous blood sample was collected before discharge. Circulating T cells were evaluated by fl ow cytometry. Tregs were defi ned as CD4 Our data suggest that Tregs might be involved in the pathogenesis of decompensated HF, and may be a novel predictor of poor prognosis in HF-REF patients. (Int Heart J 2014; 55: 271-277)

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Regulatory T Cells Ameliorate Angiotensin II–Induced Cardiac Damage

Cited by 296 publications

References 51 publications

Quantitative Phosphoproteomic Study of Pressure-Overloaded Mouse Heart Reveals Dynamin-Related Protein 1 as a Modulator of Cardiac Hypertrophy

Quantitative Phosphoproteomic Study of Pressure-Overloaded Mouse Heart Reveals Dynamin-Related Protein 1 as a Modulator of Cardiac Hypertrophy

Reduced Macrophage-Dependent Inflammation Improves Endothelin-1–Induced Vascular Injury

Prognostic Value of Circulating Regulatory T Cells for Worsening Heart Failure in Heart Failure Patients With Reduced Ejection Fraction

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