Matrine alleviates coronary microvascular dysfunction in ischemia with non-obstructive coronary artery disease mice induced by advanced glycation end products via inhibition of the reactive oxygen species-mediated endoplasmic reticulum stress in cardiac microvascular endothelial cells

doi:10.19852/j.cnki.jtcm.2025.03.006

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (3): 473-484.DOI: 10.19852/j.cnki.jtcm.2025.03.006

Matrine alleviates coronary microvascular dysfunction in ischemia with non-obstructive coronary artery disease mice induced by advanced glycation end products via inhibition of the reactive oxygen species-mediated endoplasmic reticulum stress in cardiac microvascular endothelial cells

DU Haixia¹, QIU Chuan², MA Yanpeng³^,⁴^,⁵^,⁶, PAN Shuo³^,⁴^,⁵^,⁶, WANG Xiqiang³^,⁴^,⁵^,⁶, WANG Junkui³^,⁴^,⁵^,⁶(), LIU Zhongwei³^,⁴^,⁵^,⁶()

1 Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an 710068, China; Department 403, PLA Rocket Force University of Engineering, Xi’an 710025, China
2 Division of Biomedical Informatics and Genomics, Deming Department of Medicine, Tulane Center of Biomedical Informatics and Genomics, Tulane University, New Orleans 70112, USA
3 Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an 710068, China; Scientific and Technology Transfer Office, Shaanxi Provincial People’s Hospital, Xi’an 710068, China
4 Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi’an 710003, China
5 Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People’s Hospital, Xi’an 710068, China
6 Shaanxi Belt and Road Joint Laboratory of Precision Medicine for Cardiovascular and Cerebrovascular Diseases; Xi’an 710068, China

Received:2024-03-22 Accepted:2024-09-08 Online:2025-06-15 Published:2025-05-21
Contact: Prof. LIU Zhongwei, Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an 710068, China. medicalman@163.com;Prof. WANG Junkui, Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an 710068, China. junkuiwang@yeah.net, Telephone: +86-29-85251331-3378
Supported by:
National Natural Scientific Foundation of China: Mechanisms of Macrophage-Mediated Vascular Smooth Muscle Cells Phenotypic Conversion in Advanced Glycation End Products-induced Atherosclerosis and Therapeutic Effects of Targeted Gene Silencing(82070858);Youth Scientific Research and Innovation Team Program of Shaanxi Province: Diabetes-Related Atherosclerosis Basic Research and Application Research Team(2022-SLRH-LJ-014)

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Abstract

Abstract:

OBJECTIVE: To investigate the protective effect of matrine on coronary microvascular dysfunction (CMD) induced by advanced glycation end products (AGEs) in a mouse model of ischemia with non-obstructive coronary artery disease (INOCA), with a focus on the underlying mechanisms, particularly the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK)/ nuclear factor of activated T-cells (NFAT) signaling pathway.
METHODS: An INOCA model was established in mice, and CMD was induced by peritoneal injections of AGEs. Matrine was administered daily via intraperitoneal injections. Coronary microcirculation was evaluated using coronary flow velocity reserve (CFVR), and cardiac microvascular endothelial cells (CMECs) were isolated for assessment of apoptosis, inflammation, oxidative stress, and microthrombosis. Markers of ER stress and the PERK/NFAT pathway were examined through immunoblotting, immunofluorescence, and enzymatic assays. The effect of matrine were further evaluated in CMECs treated with AGEs and the PERK agonist.
RESULTS: Matrine treatment significantly improved CFVR and reduced CMD in AGEs-exposed INOCA mice. In CMECs, matrine attenuated AGEs-induced apoptosis, inflammation, and microthrombosis. It also suppressed intracellular reactive oxygen species (ROS) generation, ER stress markers, and PERK/NFAT signaling. Matrine's effects were concentration-dependent and partially reversed by the PERK agonist, confirming its action through the ER stress pathway. No significant toxicities were observed with matrine administration.
CONCLUSION: Matrine attenuates AGEs-induced CMD in INOCA by suppressing the ROS-mediated ER stress PERK/NFAT signaling pathway in CMECs. This study highlights matrine’s potential as a therapeutic agent for CMD in diabetic cardiovascular complications.

Key words: glycation end products, advanced, matrine, endoplasmic reticulum stress, coronary microvascular dysfunction, cardiac microvascular endothelial cells

DU Haixia, QIU Chuan, MA Yanpeng, PAN Shuo, WANG Xiqiang, WANG Junkui, LIU Zhongwei. Matrine alleviates coronary microvascular dysfunction in ischemia with non-obstructive coronary artery disease mice induced by advanced glycation end products via inhibition of the reactive oxygen species-mediated endoplasmic reticulum stress in cardiac microvascular endothelial cells[J]. Journal of Traditional Chinese Medicine, 2025, 45(3): 473-484.

Figures/Tables 8

Table 1 Serum cTNT levels in animals at 0, 10 and 20 d after injections of AGEs-BSA or control BSA ($\bar{x}±s$, μg/L)

Group	n	0 d	10 d	20 d
control	6	19.3±2.8	20.6±4.2	20.6±4.2
matrine	6	19.4±1.9^a	22.7±5.6^a	22.7±5.6^a
INOCA	6	17.5±4.0^b	17.8±6.1^b	17.8±6.1^b
INOCA+AGEs	6	18.8±2.9^c	20.7±4.1^c	20.7±4.1^c
INOCA+AGEs+matrine	6	19.9±2.3^d	20.6±2.1^d	20.6±2.1^d

Table 2 CFV at rest, during hypereamia and their ratio ($\bar{x}±s$)

Group	n	CFV_rest(cm/s)	CFV_hypereamia (cm/s)	CFVR
Control	6	210.88±13.02	701.44±10.33	3.34±0.23
Matrine	6	208.42±18.54^a	695.39±15.19^a	3.37±0.33^a
INOCA	6	212.64±12.76^b	664.36±12.21^e	3.14±0.19^e
INOCA+AGEs	6	209.44±7.84^c	584.45±15.61^f	2.79±0.13^f
INOCA+AGEs+matrine	6	214.35±7.74^d	648.94±11.86^g	3.03±0.12^g

Table 3 Blood biochemical markers determination in matrine-treated animals ($\bar{x}±s$)

Biomarker	Control (n = 6)	Martine treatment (n = 6)
ALT (U/L)	31.10±3.20	30.46±3.39^a
AST (U/L)	99.10±5.27	101.08±6.31^a
CRE (mmol/L)	26.70±1.76	25.26±4.45^a
CK (U/L)	527.12±16.20	519.93±23.39^a
CK-MB (U/L)	196.02±14.51	200.32±14.82^a
Na⁺ (mmol/L)	130.71±3.07	129.91±1.51^a
K⁺(mmol/L)	4.81±0.45	5.14±0.16^a
Cl^-(mmol/L)	100.47±3.59	102.55±4.19^a

Table 4 FITC-dextran leakage and TER of CEMCs ($\bar{x}±s$)

Group	n	FITC-Dextran leakage (fold of control)	TER (Ω·cm2)
Control	6	1.02±0.08	642.14±29.75
Matrine	6	0.97±0.06^a	666.73±14.65^a
AGEs	6	2.17±0.14^b	325.75±9.47^b
AGEs+matrine	6	1.43±0.04^c	613.74±13.67^c

Figure 1 Effect of matrine on AGEs-induced coronary microcirculatory apoptosis, inflammation, and microthrombosis A: images of isolated CMECs (×400), with TUNEL-positive cells indicated by red fluorescence in Control (A1), Matrine (A2), INOCA (A3), INOCA + AGEs (A4), INOCA + AGEs + Matrine (A5). Cell nuclei were stained with DAPI; D: apoptotic rate of CMECs calculated from TUNEL staining (n = 6); B: cardiac tissue sections stained for CD45 by immunofluorescence (× 400) in Control (B1), Matrine (B2), INOCA (B3), INOCA + AGEs (B4), INOCA + AGEs + Matrine (B5). Cell nuclei were stained with DAPI; E: mean fluorescence intensities of CD45 staining (n = 6); C: cardiac tissue sections stained for CD42b by immunofluorescence (× 400) in Control (C1), Matrine (C2), INOCA (C3), INOCA + AGEs (C4), INOCA + AGEs + Matrine (C5). Cell nuclei were stained with DAPI; F: mean fluorescence intensities of CD42b staining (n = 6). Model groups: Control: treated with control BSA; matrine: treated with matrine at dosage of 200 mg/kg bodyweight; INOCA: INOCA model (ob/ob-/- mice); INOCA + AGEs: INOCA model treated with AGEs at 1 mg/d; INOCA + AGEs + matrine: INOCA model co-treated with matrine and AGEs. AGEs: advanced glycation end products; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; DAPI: 4,6-diamidino-2-phenylindole; CMECs: cardiac microvascular endothelial cells; IL6: interleukin 6; TNFα: tumor necrosis factor alpha; TXB2: thromboxane B2. Differences between two groups were compared using t-test. Data are presented as mean±standard deviation. Compared with control, aP > 0.05; compared with INOCA, bP < 0.001; compared with INOCA + AGEs, cP < 0.001.

Figure 2 Effect of matrine on AGEs-induced ROS-mediated ER signaling in CMECs A: images of isolated CMECs (× 400) with DCFH-DA fluorescent staining in Control (A1), Matrine (A2), INOCA (A3), INOCA + AGEs (A4), INOCA + AGEs + Matrine (A5). Cell nuclei were stained with DAPI ; B: mean fluorescence intensities of DCFH-DA in CMECs (n = 6); C: immunoblots of phosphorylated PERK (p-PERK), PERK, phosphorylated IRE1 (p-IRE1), and IRE1 in CMECs isolated from animals; Relative phosphorylation levels of PERK (D) and IRE1 (E) were indicated by the columns (n = 6); F: immunoblots of GRP78, ATF4, XBP1s, CHOP, and GAPDH in CMECs; Columns indicate the relative expression levels of GRP78 (G), ATF4 (H), XBP1s (I), and CHOP (J) in isolated CMECs (n = 6); K: enzymatic activity of calcineurin in isolated CMECs (n = 6). Model groups: control: treated with control BSA; matrine: treated with matrine at dosage of 200 mg/kg bodyweight; INOCA: INOCA model (ob/ob-/- mice); INOCA+AGEs: INOCA model treated with AGEs at 1 mg/d; INOCA + AGEs + matrine: INOCA model co-treated with matrine and AGEs. AGEs: advanced glycation end products; ROS: reactive oxygen species; DAPI: 4,6-diamidino-2-phenylindole; CMECs: cardiac microvascular endothelial cells; DCFH-DA: 2,7-dichlorofluorescein; PERK: protein kinase R-like endoplasmic reticulum kinase; IRE1: inositol-requiring enzyme 1; GRP78: glucose regulated protein 78; ATF4: activating transcription factor 4; XBP1s: X-box binding protein 1s; CHOP: C/EBP-homologous protein. Differences between two groups were compared using t-test. Data are presented as mean ± standard deviation. Compared with control, aP > 0.05; compared with INOCA, bP < 0.001; compared with INOCA + AGEs, cP < 0.001.

Figure 3 Effect of matrine on NFAT-mediated pathways in CMECs A: immunofluorescent staining of NFATc4 in isolated CMECs in Control (A1), Matrine (A2), INOCA (A3), INOCA + AGEs (A4), INOCA + AGEs + Matrine (A5). Cell nuclei were stained with DAPI; B: NFATc4 nuclear translocation rate (n = 6); C: immunoblots of NFATc4 and histone H3 in nuclear protein extracted from CMECs; D: relative nuclear translocation of NFATc4 (n = 6); E: immunoblots of COX2, IL6, TNFα, Fas, FasL, and GAPDH in isolated CMECs; F-J: relative expression levels of COX2 (F), FAS (G), FASL (H), IL6 (I), and TNFα (J) (n = 6). Model groups: Control: treated with control BSA; matrine: treated with matrine at dosage of 200 mg/kg bodyweight; INOCA: INOCA model (ob/ob-/- mice); INOCA + AGEs: INOCA model treated with AGEs at 1 mg/d; INOCA + AGEs + matrine: INOCA model co-treated with matrine and AGEs. AGEs: advanced glycation end products; DAPI: 4,6-diamidino-2-phenylindole; CMECs: cardiac microvascular endothelial cells; NFAT: nuclear factor of activated T-cells; COX2: cyclooxygenase 2; IL6: interleukin 6; TNFα: tumor necrosis factor alpha; FASL: FAS ligand. Differences between two groups were compared using t-test. Data are presented as mean ± standard deviation. Compared with control, aP > 0.05; compared with INOCA, bP < 0.001; compared with INOCA + AGEs, cP < 0.001; compared with INOCA + AGEs, dP < 0.01.

Figure 4 Effect of matrine on AGEs-induced PERK/NFAT signaling in primary CMECs A: immunoblots of p-PERK, PERK, and GAPDH in primary CMECs treated with CCT020312; B: relative phosphorylation levels of PERK (n = 3). Compared with control, aP < 0.05; C: immunoblots of NFATc4 and histone H3 in AGEs-exposed primary CMECs treated with matrine and/or CCT020312; D: relative nuclear levels of NFATc4 (n = 3); E: immunoblots of GRP78, p-PERK, PERK, p-IRE1α, IRE1α, XBP1s, ATF4, CHOP, and GAPDH in AGEs-exposed primary CMECs treated with matrine and/or CCT020312; F: relative expression level of GRP78 (n = 3); G: relative phosphorylation level of IRE1α (n = 3); H: relative expression level of XBP1s (n = 3); I: relative phosphorylation level of PERK (n = 3); J: relative expression level of ATF4 (n = 3); K: relative expression level of CHOP (n = 3). Model groups: control: untreated primary CMECs; primary CMECs treated with CCT020312 at 10 μmol/L. AGEs: advanced glycation end products; CMECs: cardiac microvascular endothelial cells; NFAT: nuclear factor of activated T-cells; PERK: protein kinase R-like endoplasmic reticulum kinase; IRE1: inositol-requiring enzyme 1; GRP78: glucose regulated protein 78; ATF4: activating transcription factor 4; XBP1s: X-box binding protein 1s; CHOP: C/EBP-homologous protein. Differences between two groups were compared using t-test. Data are presented as mean ± standard deviation. Compared with control CMECs, aP > 0.05; compared with CMECs treated with matrine at 1.0 mmol/L, bP < 0.05; compared with CMECs treated with AGEs, cP < 0.05; compared with CMECs co-treated with matrine at 0.25 mmol/L and AGEs, dP < 0.05; compared with CMECs co-treated with matrine at 0.5 mmol/L and AGEs, eP < 0.05; CMECs co-treated with matrine at 1.0 mmol/L and AGEs, fP < 0.05.

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Matrine alleviates coronary microvascular dysfunction in ischemia with non-obstructive coronary artery disease mice induced by advanced glycation end products via inhibition of the reactive oxygen species-mediated endoplasmic reticulum stress in cardiac microvascular endothelial cells

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