Dataset Information

Complement C1q-induced activation of ?-catenin signalling causes hypertensive arterial remodelling.

ABSTRACT: Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates ?-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of ?-catenin signalling in hypertensive arterial remodelling. Activation of ?-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of ?-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced ?-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of ?-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension.

SUBMITTER: Sumida T

PROVIDER: S-EPMC4351572 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling.

Sumida Tomokazu T Naito Atsuhiko T AT Nomura Seitaro S Nakagawa Akito A Higo Tomoaki T Hashimoto Akihito A Okada Katsuki K Sakai Taku T Ito Masamichi M Yamaguchi Toshihiro T Oka Toru T Akazawa Hiroshi H Lee Jong-Kook JK Minamino Tohru T Offermanns Stefan S Noda Tetsuo T Botto Marina M Kobayashi Yoshio Y Morita Hiroyuki H Manabe Ichiro I Nagai Toshio T Shiojima Ichiro I Komuro Issei I

Nature communications 20150226

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates β-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of ...[more]

PMID: 25716000

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Project description:Evidence has been accumulating for a role of inflammation in the development of Alzheimer's disease (AD), a progressive neurodegenerative disorder causing a common form of dementia in the elderly. C1q, part of the initiation component of the classical complement pathway (CCP), is associated with beta-sheet, fibrillar amyloid plaques in AD brain. In vitro, beta-amyloid peptide in fibrillar beta-sheet conformation (fAbeta) can activate CCP via interaction of specific negatively charged amino acids of the beta-amyloid fibril with human C1q. Previous results using peptide inhibitors led to the hypothesis that a highly positively charged domain consisting of three arginine residues, such as that present in the N-terminal collagen-like region of the human C1q A chain, may be critical for the activation event. However, mouse C1q A chain lacks two of the three arginines in the corresponding C1q A chain collagen-like region. To test the hypothesis that this divergent activation domain results in a weaker C' activation and thus may contribute to the lower neuronal loss observed in transgenic mouse models of AD, a partially humanized C1q A chain knock-in mouse was generated. The mouse C1q A chain gene was modified by homologous recombination to replace 4 residues in the 13-20 amino acid region to mimic the corresponding sequence from human A chain. No significant differences in the expression of C1q were found in sera from mice homozygous for the humanized C1q A chain compared to littermate wild type mice. Two distinct C1 activation assays demonstrated that activation by fAbeta was not significantly different in the homozygous humanized C1q A chain mice. Activation of C1 by DNA, previously hypothesized to interact with this C1q A chain arginine-rich sequence was also not significantly different in the knock-in mouse. Molecular modeling based on the published crystal structure of human C1q B chain globular head and a beta-sheet model for fibrillar amyloid suggests an alternative arginine ladder in the globular head domain may provide the functional C1 activating interaction domains. The humanized C1q mouse generated here should provide a better animal model for assessing the mechanisms of C1 activation and the contribution of C1q to human health and disease.

Dataset Information

Complement C1q-induced activation of ?-catenin signalling causes hypertensive arterial remodelling.

Publications

Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling.

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