Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease.

Shichao Zhu,Nan Chen,Yuyi Tang,Mieradilijiang Abudupataer,Jingjing Zhang,Jun Li,Chunsheng Wang,Md Fazle Alam,Guoquan Yan,Shiqiang Yan,Kehua Xu,Shaman Luo,Weijia Zhang,Kai Zhu,Wenrui Ma,Hao Lai,Hui Huang,Li Wang

doi:10.7554/elife.69310

Abstract

Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs). Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients. The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA. National Key R and D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

Highlights

Bicuspid aortic valve (BAV) disease is the most common congenital cardiovascular abnormality and is found in nearly 1.4% of the general population
We evaluated the expression of mitochondrial fission- and fusion-related proteins in non-diseased and BAV-thoracic aortic aneurysm (TAA) aortic tissues
Protein analyses of human aortic aneurysm tissues suggested the insufficient expression of NOTCH1 in BAV-related thoracic aortic aneurysm (BAV-TAA) was associated with the impaired mitochondrial dynamics and oxidative phosphorylation (OXPHOS)

Summary

Introduction

Bicuspid aortic valve (BAV) disease is the most common congenital cardiovascular abnormality and is found in nearly 1.4% of the general population It is not known how these findings are connected or linked with the aneurysms developing To answer this question, Abudupataer et al analyzed the proteins present in diseased and healthy aortic muscle cells, confirming a lower production of NOTCH1 and impaired mitochondria in diseased tissues. BAV arises from incomplete separation or fusion of the aortic valve cusps and is associated with an approximately 40% risk of developing thoracic aortic aneurysm (TAA), namely, bicuspid aortopathy (Verma and Siu, 2014). In a mice model of abdominal aortic aneurysm (AAA), impaired mitochondrial dynamics was found to play salient roles in disease development, and could be attenuated by the mitochondrial fission inhibitor Mdivi (Cooper et al, 2021) These studies focused on the analysis of abdominal aortic aneurysms and genetic TAA with FBN1 or Fubulin-4 mutation. Our study provides the first demonstration previously undocumented role of impairment of mitochondrial fusion in bicuspid aortopathy, which may serve as a potential pharmacological target for preventing disease progression

Materials and methods

Results

Discussion