Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model
Taisuke Kato, … , Shoji Tsuji, Osamu Onodera
Taisuke Kato, … , Shoji Tsuji, Osamu Onodera
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e140555. https://doi.org/10.1172/JCI140555.
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Research Article Neuroscience Vascular biology

Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model

Abstract

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1−/− mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Authors

Taisuke Kato, Ri-ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

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Figure 1

Matrisome protein accumulation with FN as a central hub in cerebral vessels in HTRA1−/− mice.

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Matrisome protein accumulation with FN as a central hub in cerebral vess...
(A) GO enrichment analysis of changed proteins in the cerebral arteries of HTRA1−/− mice. The plots are size-scaled by the number of changed proteins enriched for each GO term and color-scaled by gene ratio (ratio of the number of changed proteins to the number of proteins associated with a GO term). BP: biological process, CC: cellular component, MF: molecular function. (B) Heatmap of proteome data showing the abundance of matrisome proteins expressed as the log2 ratio of the average abundance in HTRA1+/+ mice (n = 3 animals per group). The upper section (changed) shows data for proteins with an adjusted P < 0.05 and a fold change in protein abundance > 1.5 or < 1.5−1. The lower section (unchanged) shows data for proteins that did not reach the set thresholds. (C) Protein-protein interaction network composed of fluctuating matrisome proteins. The nodes are size-scaled by degree and color-scaled by betweenness centrality (CB). Proteins (nodes) without interactions (edges) are not shown. (D) Scatter plot of the results of network topology analysis including degree and CB revealing FN (Fn1) as a major hub in the network.