Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis

Feng，Yan hai1,2; Li，Ling fei3; Zhang，Qiong1,2; Zhang，Jun hui4; Huang，Yao1,2; Lv，Yan ling1,2; Jia，Jie Zhi1,2; Zhang，Dongxia1,2; Hu，Jiong Yu2,4; Huang，Yue Sheng1,2,5

2021-12-01

10.1038/s41420-021-00606-w

Cell Death Discovery   Impact Factor & Quartile

2058-7716

Phosphorylation of MAP4 (p-MAP4) causes cardiac remodeling, with the cardiac microvascular endothelium being considered a vital mediator of this process. In the current study, we investigated the mechanism underlying p-MAP4 influences on cardiac microvascular density. We firstly confirmed elevated MAP4 phosphorylation in the myocardium of MAP4 knock-in (KI) mice. When compared with the corresponding control group, we detected the decreased expression of CD31, CD34, VEGFA, VEGFR2, ANG2, and TIE2 in the myocardium of MAP4 KI mice, accompanied by a reduced plasma concentration of VEGF. Moreover, we observed apoptosis and mitochondrial disruption in the cardiac microvascular endothelium of MAP4 KI animals. Consistently, we noted a decreased cardiac microvascular density, measured by CD31 and lectin staining, in MAP4 KI mice. To explore the underlying mechanism, we targeted the NLRP3-related pyroptosis and found increased expression of the corresponding proteins, including NLRP3, ASC, mature IL-1β, IL-18, and GSDMD-N in the myocardium of MAP4 KI mice. Furthermore, we utilized a MAP4 (Glu) adenovirus to mimic cellular p-MAP4. After incubating HUVECs with MAP4 (Glu) adenovirus, the angiogenic ability was inhibited, and NLRP3-related pyroptosis were significantly activated. Moreover, both cytotoxicity and PI signal were upregulated by the MAP4 (Glu) adenovirus. Finally, NLRP3 inflammasome blockage alleviated the inhibited angiogenic ability induced by MAP4 (Glu) adenovirus. These results demonstrated that p-MAP4 reduced cardiac microvascular density by activating NLRP3-related pyroptosis in both young and aged mice. We thus managed to provide clues explaining MAP4 phosphorylation-induced cardiac remodeling and enriched current knowledge regarding the role of MAP4.

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WOS:000684221200001

2-s2.0-85112305113

Scopus

1.Laboratory Institute of Burn Research,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
2.State Key Laboratory of Trauma,Burns and Combined Injury,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
3.Department of Dermatology,Daping Hospital,Third Military Medical University (Army Medical University),Chongqing,China
4.Endocrinology Department,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
5.Department of Wound Repair,Institute of Wound Repair,Shenzhen People’s Hospital,First Affiliated Hospital of Southern University of Science and Technology,Shenzhen,China

Feng，Yan hai,Li，Ling fei,Zhang，Qiong,et al. Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis[J]. Cell Death Discovery,2021,7(1).

Feng，Yan hai.,Li，Ling fei.,Zhang，Qiong.,Zhang，Jun hui.,Huang，Yao.,...&Huang，Yue Sheng.(2021).Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis.Cell Death Discovery,7(1).

Feng，Yan hai,et al."Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis".Cell Death Discovery 7.1(2021).