CALHM5 deficiency alleviates aortic aneurysm by regulating smooth muscle calcium homeostasis
Abstract
Ion channels are the second most common clinical drug target besides G protein–coupled receptors. Aneurysmal diseases pose a significant threat to human life. Novel drug targets for its treatment remain to be explored. We investigated the role of an ion channel, calcium homeostasis modulators 5 (CALHM5), on the development of aortic aneurysms. We characterized CALHM5 as a plasma membrane ion channel abundant in smooth muscle cells of both humans and mice, playing a pivotal role in regulating calcium homeostasis. Notably, CALHM5 deficiency suppressed the transcription of the L-type calcium channel (LTCC) pore-forming subunit by downregulating cAMP-response element binding proteins. This in turn diminished blood vessel contractility and decreased blood flow. Intriguingly, CALHM5 expression is downregulated in smooth muscle tissues of aortic aneurysm patients. Furthermore, CALHM5 deficiency was observed to ameliorate the development of abdominal aortic aneurysms in mice, partly by stimulating smooth muscle cell proliferation. CALHM5 emerges as an ion channel prominently expressed in arterial smooth muscles, serving as a physiological regulator of smooth muscle contraction and presenting itself as a promising therapeutic target for aortic aneurysms.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Bo Yang
Ting Xu
Qianqian Yang
Liangzhu Mo
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Jianyi Huo
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Taiyang Mu
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Yating Zhi
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Yun Du
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Haojie Wang
Wuhan National Laboratory for Optoelectronics
Lingchuan Guo
Department of Pathology, The First Affiliated Hospital of Soochow University
Zhen Zhu
Academy for Advanced Interdisciplinary Studies
Yulong Feng
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Yu Rui
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University
Li Zhu
William A. Coetzee
Departments of Pathology, Neuroscience and Physiology, Biochemistry and Molecular Pharmacology, Medicine, and New York University School of Medicine
Qinqin Gao
Institute for Fetology, Department of Pathology, First Affiliated Hospital of Soochow University
Hua-Qian Yang
Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Cyrus Tang Medical Institute, Medical College of Soochow University