Theranostics 2020; 10(12):5581-5599. doi:10.7150/thno.44687 This issue Cite
1. Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College,1 Xian Nong Tan Street, Beijing 100050, China.
2. The State Key Laboratory of Bioactive Substance and Function of Natural Medicines 1 Xian Nong Tan Street, Beijing 100050, China
3. Beijing Key Laboratory of Drug Targets Identification and Drug Screening Beijing 100050, China.
4. Department of anesthesiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing 100029, China.
# Co-first authors: Prof. Lan Sun, Dr. Peirong Lin, and Ying Chen.
Rationale: There is a continued need for investigating the roles of microRNAs and their targets on the pathogenesis of pulmonary arterial hypertension (PAH) vascular remodeling. We recently identified the association of myeloid miR-182-3p and its new target, Myeloid-Associated Differentiation Marker (Myadm), with vascular remodeling. Here, we aimed to determine the role of miR-182-3p/Myadm on PAH vascular remodeling and the underlying molecular mechanism.
Methods: The miR-182-3p/Myadm expression profiles were detected in PAH patients and experimental rodent models. Loss-of-function and gain-of-function studies using gene knock-in or gene knock-out and the combinations of the proteomic technology and genome-wide ChIP-Seq were employed to determine the downstream targets of miR-182-3p/Myadm in response to monocrotaline (MCT)-induced PAH.
Results: The miR-182-3p/Myadm expression was altered in PAH patients and experimental rodent models. Both miR-182-3p inhibitor and overexpression of Myadm augmented the pathological progression in rats in response to MCT-induced PAH. In contrast, miR-182-3p mimic and Myadm gene knockout attenuated the changes in the hemodynamics and structure of the cardio-pulmonary system in MCT-induced PAH in rats. Myadm mediated the proliferation of pulmonary artery smooth muscle cells (PASMCs) by altering the cell cycle kinase inhibitor (p21/Cip1) expression through the transcription factor Krüppel-like factor 4 (KLF4) translocation into the cytoplasm.
Conclusion: Our findings indicate the prognostic and therapeutic significance of miR-182-3p in PAH and provide a new regulatory model of the myeloid-derived miR-182-3p/Myadm/KLF4/p21 axis in PAH vascular remodeling.
Keywords: pulmonary artery hypertension, microRNA, myeloid, vascular remodeling, p21/Cip1.