Deletion of the <scp>EGF</scp> receptor in vascular smooth muscle cells prevents chronic angiotensin <scp>II</scp>‐induced arterial wall stiffening and media thickening

Schreier, Barbara; Hünerberg, Mirja; Mildenberger, Sigrid; Rabe, Sindy; Bethmann, Daniel; Wickenhauser, Claudia; Gekle, Michael

doi:10.1111/apha.12996

Cited by 26 publications

(45 citation statements)

References 65 publications

(101 reference statements)

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“…In contrast to the above mentioned studies, we could not observe an increase in miR-221 or miR-222 in cardiac fibroblasts of mice with genetic heart hypertrophy. This might be due to the fact that in our mouse models, no signs of heart failure could be observed, e.g., lung weight per tibia length, a measure for lung congestion, was not altered [17,42].…”

Section: Discussionmentioning

confidence: 87%

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

Binas

Knyrim

Hupfeld

et al. 2019

Cell. Mol. Life Sci.

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MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among others cardiac hypertrophy and atrial fibrillation. The aim of our study was to evaluate the impact of miR-221/222 on cardiac electrical remodeling. Cardiac miR expression was analyzed in a mouse model with altered electrocardiography parameters and severe heart hypertrophy. Next generation sequencing revealed 14 differentially expressed miRs in hypertrophic hearts, with miR-221 and-222 being the strongest regulated miR-cluster. This increase was restricted to cardiomyocytes and not observed in cardiac fibroblasts. Additionally, we evaluated the change of miR-221/222 in vivo in two models of pharmacologically induced heart hypertrophy (angiotensin II, isoprenaline), thereby demonstrating a stimulus-induced increase in miR-221/222 in vivo by angiotensin II but not by isoprenaline. Whole transcriptome analysis by RNA-seq and qRT-PCR validation revealed an enriched number of downregulated mRNAs coding for proteins located in the T-tubule, which are also predicted targets for miR-221/222. Among those, mRNAs were the L-type Ca 2+ channel subunits as well as potassium channel subunits. We confirmed that both miRs target the 3′-untranslated regions of Cacna1c and Kcnj5. Furthermore, enhanced expression of these miRs reduced L-type Ca 2+ channel and Kcnj5 channel abundance and function, which was analyzed by whole-cell patch clamp recordings or Western blot and flux measurements, respectively. miR-221 and-222 contribute to the regulation of L-type Ca 2+ channels as well as Kcnj5 channels and, therefore, potentially contribute to disturbed cardiac excitation generation and propagation. Future studies will have to evaluate the pathophysiological and clinical relevance of aberrant miR-221/222 expression for electrical remodeling. Keywords Electrical remodeling • Cardiomyocytes • Angiotensin II • Heart hypertrophy Abbreviations ANOVA Analysis of variance AUC Area under the curve AII Angiotensin II Bp Base pair BW Body weight Cacna1C Calcium voltage-gated channel subunit α1 C, L-type Cacnb2 Calcium voltage-gated channel auxiliary subunit β2 Cacna2d1 Voltage-dependent calcium channel subunit α2/δ1 Cav1.2 L-type Ca 2+ channel CCH Carbachol, acetylcholine analog cDNA Complementary DNA CE Carbachol effect CM Cardiomyocyte ddPCR Droplet digital PCR Cellular and Molecular Life Sciences

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Section: Discussionmentioning

confidence: 87%

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

Binas

Knyrim

Hupfeld

et al. 2019

Cell. Mol. Life Sci.

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“…EGFR activation has been implicated in vascular remodelling in mice infused with AngII [32,33]. Deletion of EGFR in vascular smooth muscle cells prevents AngII-induced vascular remodelling [34], while pharmacological inhibition of EGFR limits development of experimental AAA [31]. It has been previously reported that plasma kallikrein stimulates ADAM-17 activity in vascular smooth muscle cells via a bradykinin-independent mechanism involving EGFR activation and EGFR-dependent Erk1 signalling [35].…”

Section: Discussionmentioning

confidence: 99%

Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice

et al. 2020

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Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein–kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.

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“…Further, they evaluate the expression of a number of genes related to fibrotic reactions and measure aortic media thickness as well as dynamic parameters such as potassium‐induced constriction of the arteries. The authors conclude from their results that vascular smooth muscle cell‐EGFRs are relevant for pathological angiotensin II action in vivo with respect to renal end‐organ damage …”

mentioning

confidence: 94%

“…Inducible knock out models have been proven to be a valuable tool in cardiovascular research. In a work by Schreier et al, the role of a deletion of the epidermal growth factor (EGF) receptor in vascular smooth muscle cells is investigated in detail. In the work, the authors evaluate the relevance of this protein during chronic angiotensin II challenge.…”

mentioning

confidence: 99%

Recent advances in hypertension research

Mrowka

2019

Acta Physiologica

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Deletion of the EGF receptor in vascular smooth muscle cells prevents chronic angiotensin II‐induced arterial wall stiffening and media thickening

Cited by 26 publications

References 65 publications

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice

Recent advances in hypertension research

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