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. 2023 Apr 24;28(9):3687.
doi: 10.3390/molecules28093687.

Polygonum orientale L. Alleviates Myocardial Ischemia-Induced Injury via Activation of MAPK/ERK Signaling Pathway

Changli Fu  1   2 , Mingjin Wang  1   2 , Yuan Lu  3 , Jie Pan  1 , Yueting Li  3 , Yongjun Li  1 , Yonglin Wang  3 , Aimin Wang  1 , Yong Huang  3 , Jia Sun  3 , Chunhua Liu  1
Affiliations

Polygonum orientale L. Alleviates Myocardial Ischemia-Induced Injury via Activation of MAPK/ERK Signaling Pathway

Changli Fu et al. Molecules. .

Abstract

Although Polygonum orientale L. (PO) has a beneficial effect on treatment of myocardial ischemia (MI), its mechanism remains unclear. This study aimed to explore the pharmacological mechanism of PO against MI through MAPK signaling pathways. Firstly, the therapeutic effect of PO was evaluated for treatment of MI mice. Using Western blot and immunohistochemistry, the influence of PO on MAPK signaling pathways and cell apoptosis was investigated. Subsequently, one key pathway (ERK) of MAPK signaling pathways was screened out, on which PO posed the most obvious impact. Finally, an inhibitor of ERK1/2 was utilized to further verify the regulatory effect of PO on the MAPK/ERK signaling pathway. It was found that PO could reduce the elevation of the ST segment; injury of heart tissue; the activity of LDH, CK, NOS, cNOS and iNOS and the levels of NO, BNP, TNF-α and IL-6. It is notable that PO could significantly modulate the protein content of p-ERK/ERK in mice suffering from MI but hardly had an effect on p-JNK/JNK and p-p38/p38. Additionally, the expressions of bax, caspase3 and caspase9 were inhibited in heart tissue in the PO-treated group. To evaluate whether ERK1/2 inhibitor (PD98059) could block the effect of PO on treatment of MI, both PO and PD98059 were given to mice with MI. It was discovered that the inhibitor indeed could significantly reverse the regulatory effects of PO on the above indicators, indicating that PO could regulate p-ERK/ERK. This study provides experimental evidence that PO extenuates MI injury, cardiomyocyte apoptosis and inflammation by activating the MAPK/ERK signaling pathway.

Keywords: MAPK signaling pathway; Polygonum orientale L.; myocardial ischemia.

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Conflict of interest statement

The authors declare that there are no conflict of interest in this study.

Figures

Figure 1
Figure 1
BPC of PO extract and mixed reference solution using UHPLC–Q-Exactive Orbitrap Plus HRMS. (A) BPC of mixed reference solution in positive ion modes. (B) BPC of mixed reference solution in negative ion modes. (C) BPC of PO extract in positive ion modes. (D) BPC of PO extract in negative ion modes. (1: protocatechuic acid, 2: isoorientin, 3: orientin, 4: vitexin, 5: quercetin, 6: N-p-trans-coumaroyltyramine, 7: N-trans-feruloyltyramine).
Figure 2
Figure 2
The effect of PO on ST segment. (A) Sham group. (B) MI group. (C) PO group. (D) DS group. (Mean ± SD, n = 6, *** p < 0.001 vs. MI group; # p < 0.05, ## p < 0.01 vs. MI group).
Figure 3
Figure 3
PO regulates MI injury, coronary artery contraction and relaxation and inflammatory in MI mice. (A) LDH. (B) CK. (C) NOS. (D) iNOS. (E) cNOS. (F) NO. (G) IL-6. (Mean ± SD, n = 6, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. MI group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. MI group).
Figure 4
Figure 4
PO reduces apoptosis resulting from MI. (A) The protein expressions of bax and caspase3. (B,C) Quantitative analysis of bax and caspase3. (Mean ± SD, n = 3, ** p < 0.01, *** p < 0.001 vs. MI group; ## p < 0.001, ### p < 0.001 vs. MI group).
Figure 5
Figure 5
Effect of PO on MAPK signaling pathways. (A) Western blot bands of p38 and p-p38. (B) Western blot bands of JNK and p-JNK. (C) Western blot bands of ERK1/2 and p-ERK1/2. (D) Quantitative analysis of p-p38/p38. (E) Quantitative analysis of p-JNK/JNK. (F) Quantitative analysis of p-ERK1/2/ERK1/2. (Mean ± SD, n = 3, * p < 0.05 vs. MI group, ## p < 0.01 vs. MI group).
Figure 6
Figure 6
Involvement of ERK pathway in the cardioprotective effect of PO on MI mice. (A) Western blot bands and quantitative analysis of ERK and p-ERK1/2, n = 3. (B) Immunohistochemistry and quantitative analysis of ERK and p-ERK1/2, n = 4. (C) PO decreases the ST segment, n = 6. (D) PO improves myocardial pathological injury, n = 4. (E–J) The activities of LDH, CK, iNOS, NOS and cNOS in serum, n = 6. (K–M) The level of BNP, IL-6 and TNF-α in serum, n = 6. (Mean ± SD, *p < 0.05, ** p < 0.01, *** p < 0.001 vs. MI group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. MI group; @ p < 0.05, @@ p < 0.01, @@@ p < 0.001 vs. PO group).
Figure 6
Figure 6
Involvement of ERK pathway in the cardioprotective effect of PO on MI mice. (A) Western blot bands and quantitative analysis of ERK and p-ERK1/2, n = 3. (B) Immunohistochemistry and quantitative analysis of ERK and p-ERK1/2, n = 4. (C) PO decreases the ST segment, n = 6. (D) PO improves myocardial pathological injury, n = 4. (E–J) The activities of LDH, CK, iNOS, NOS and cNOS in serum, n = 6. (K–M) The level of BNP, IL-6 and TNF-α in serum, n = 6. (Mean ± SD, *p < 0.05, ** p < 0.01, *** p < 0.001 vs. MI group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. MI group; @ p < 0.05, @@ p < 0.01, @@@ p < 0.001 vs. PO group).
Figure 7
Figure 7
PO reduces the apoptosis related proteins through activating ERK signaling pathway. (A) Western blot bands of casepase3, caspase9 and bax. (B–D) Quantitative analysis of casepase3, caspase9 and bax. (Mean ± SD, n = 3, * p < 0.05, *** p < 0.001 vs. MI group; ## p < 0.01, ### p < 0.05 vs. MI group; @ p < 0.05, @@ p < 0.01 vs. PO group).
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