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 8

Candesartan treatment downregulates vascular matrisome gene expression.

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Candesartan treatment downregulates vascular matrisome gene expression. ...
(A and B) Volcano plot of gene expression in the anterior and middle cerebral arteries of untreated HTRA1−/− mice and HTRA1−/− mice subjected to short-term (1 week) (A) or long-term (from 4 to 24 months of age) (B) candesartan treatment according to RNA-seq analysis (n = 3 animals per group). The threshold for differential expression was set to an adjusted P < 0.05. Data exceeding the threshold are shown in the red plot. (C) The Venn diagram illustrates a gene (Adamtsl2) that overlapped between the gene sets that were differentially expressed in the cerebral arteries of HTRA1−/− mice subjected to short-term and long-term candesartan treatment according to the RNA-seq analysis. (D and E) ddPCR analysis using an increasing number of samples confirmed the reducing effect of candesartan on Adamtsl2 expression (n = 5–6 animals per group). A similar analysis was performed on amlodipine-treated HTRA1−/− mouse samples. (F) We quantified the level of each mRNA by ddPCR using total RNA extracted from the arteries of 4-month-old HTRA1+/+ and HTRA1−/− mice with or without 1 week candesartan or amlodipine treatment (n = 5–6 animals per group). The bar graphs show values relative to those for HTRA1+/+ mice. The red dots represent samples used for RNA-seq analysis, and the black dots indicated additional samples that were collected, and cDNA was prepared at the same time. The data represent the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001 with Bonferroni’s post hoc test (D–F).