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Journal of Peking University (Health Sciences) ›› 2020, Vol. 52 ›› Issue (5): 856-862. doi: 10.19723/j.issn.1671-167X.2020.05.010

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Association of CMTM5 gene expression with the risk of in-stent restenosis in patients with coronary artery disease after drug-eluting stent implantation and the effects and mechanisms of CMTM5 on human vascular endothelial cells

Teng-fei LIU,Tao LIN,Li-hui REN,Guang-ping LI,Jian-jun PENG()   

  1. Department of Cardiology, Shijitan Hospital, Beijing 100034, China
  • Received:2018-11-15 Online:2020-10-18 Published:2020-10-15
  • Contact: Jian-jun PENG E-mail:pjj1972@sina.com
  • Supported by:
    Foundation of Research and Development Plan of China Railway Corporation(J2017Z608);Youth Foundation of Central Laboratory of Beijing Shijitan Hospital Affiliated to the Capital Medical University(2017-q27);Open Research Funding of Central Laboratory of Beijing Shijitan Hospital Affiliated to the Capital Medical University(2019-KF28)

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Abstract:

Objective: To elucidate the correlation between CKLF-like marvel transmembrane domain containing member (CMTM5) gene and the risk of in-stent restenosis (ISR) with coronary artery disease (CAD) patients and to detect the effects and mechanisms of CMTM5-stimulated genes on human vascular endothelial cells (ECs) proliferation and migration. Methods: A total of 124 hospitalized patients in Shijitan Hospital were enrolled in this study. All the CAD patients were detected with platelet reactivity and grouped into two groups according to platelet reactivity; ISR was conformed by coronary angiography; RT-PCR method was used to detect CMTM5 gene expression; The CMTM5 over expression, reduction and control EC lines were established; Cell count, MTT, Brdu and flow cytometry methods were used to detect the proliferation of ECs, scratch and transwell experiments to test the migration of ECs, Western blot was used to detect signal path expressions. Results: CMTM5 gene expression in HAPR (High on aspirin platelet reactivity) group was 1.72 times compared with No-HAPR group, which was significantly higher than No-HAPR group. HAPR group ISR rate was 25.8% (8 cases), the incidence of No-HAPR ISR group was 9.7% (9 cases), and the results showed that in HAPR group, the incidence of ISR was significantly higher than that in No-HAPR group (P=0.04, OR=0.04, 95%CI=1.16-7.52), which showed that CMTM5 gene was significantly correlated with the risk of ISR. In HAPR group ISR rate was 25.8% (8 cases), the incidence of ISR in No-HAPR group was 9.7% (9 cases), and the results showed that the risk of ISR in HAPR group was significantly higher than that in No-HAPR group. All the results showed that CMTM5 was significantly correlated with the risk of ISR in CAD patients (P<0.05). CMTM5 overexpression inhibited the proliferation and migration ability of ECs (P<0.05), PI3K/Akt signaling pathways were involved in the role of regulation on ECs. Conclusion: Our results revealed that CMTM5 gene was closely related with ISR, CMTM5 overexpression may repress ECs proliferation and migration through regulating PI3K-Akt signaling.

Key words: Platelet reactivity, CKLF-like marvel transmembrane dimain containing member 5, Coronary artery diseases, In-stent restenosis

CLC Number: 

  • R543.3

Table 1

Baseline characteristics of the patients in HAPR and No-HAPR groups"

Variables HAPR(n=31) No-HAPR(n=93) P
Age/years, x-±s 76.3±7.3 74.8±8.9 0.063
Male, n(%) 27(87.1) 72(77.4) 0.308
BMI/(kg/m2), x-±s 26.1±3.3 24.5±3.1 0.451
Hypertension, n(%) 25(80.6) 66(71.0) 0.354
Diabetes, n(%) 12(38.7) 32(34.4) 0.670
Current smoking, n(%) 11(35.5) 15(16.1) 0.039*
Hyperlipidemia, n(%) 27(87.1) 75(80.6) 0.589
Essential medicines, n(%) 14(45.2) 55(59.1) 0.212
ACEI/ARB 22(70.9) 61(65.6) 0.663
β-blocker 12(38.7) 45(48.4) 0.408
CCB 13(41.9) 31(33.3) 0.395
Nitrates 24(77.4) 81(87.1) 0.249
Stains 27(87.1) 72(77.4) 0.308
Cardiovascular events, n(%) 8 (25.8) 9 (9.7) 0.037

Table 2

COX regression analysis for the potential risk factors of cardiovascular events"

Risk factors HR 95%CI P
ΔCt CMTM5 0.086 0.053-0.099 0.010
Current smoking 1.998 1.050-3.802 0.035

Figure 1

Overexpression of CMTM5 attenuated the proliferation of ECs in vitro *P <0.05, n≥3. A and B, cell counting and MTT assay revealed that overexpression of CMTM5 inhibited the proliferation of ECs;C and D, FCM assay showed the percentage of S+G2 phase cells was significantly lower than that in EN and EO-mock groups (P<0.05). EN, non-infected endothelial cells; EO, CMTM5 overexpression endothelial cells; EO-mock, ad-mock infected endothelial cells. "

Figure 2

CMTM5 inhibition promoted the proliferation of ECs in vitro *P <0.05, n≥3. A and B, cell counting and MTT assay showed that CMTM5 suppression facilitated the growth of ECs;C and D, BrdU incorporation assay revealed the proliferation-promoting effect of CMTM5;E and F, using FCM assay, the percentage of S+G2 phase cells in ES group was significantly higher than that in EN and ES-mock group (P<0.05). EN, non-infected endothelial cells; ES, CMTM5 suppression endothelial cells; ES-mock, lenti-mock infected endothelial cells. "

Figure 3

Effects of CMTM5 changes on the migration of ECs * P<0.05, n≥3. EN, non-infected endothelial cells; EO, CMTM5 overexpression endothelial cells; EO-mock, ad-mock infected endothelial cells; ES, CMTM5 suppression endothelial cells; ES-mock, lenti-mock infected endothelial cells. "

Figure 4

Effects of CMTM5 on ECs migration *P<0.05, n≥3. EN, non-infected endothelial cells; EO, CMTM5 overexpression endothelial cells; EO-mock, ad-mock infected endothelial cells; ES, CMTM5 suppression endothelial cells; ES-mock, lenti-mock infected endothelial cells. "

Figure 5

The effects of CMTM5 levels on the PI3K/Akt pathway proteins *P<0.05, n≥3. A and B, The protein levels of p-Akt in ES group was significantly higher than than in EN and ES-mock groups (P<0.05);C and D, the protein levels of p-Akt in EO group were significantly lower than that in EN and EO-mock groups (P<0.05). EN, non-infected endothelial cells; EO, CMTM5 overexpression endothelial cells; EO-mock, ad-mock infected endothelial cells; ES, CMTM5 suppression endothelial cells; ES-mock, lenti-mock infected endothelial cells. "

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