Perillaldehyde reduces myocardial ischemia-reperfusion injury in rats by inhibiting MAPK1

Myocardial ischemia-reperfusion (MI/RI) injury is a type of cardiac damage that occurs during the reperfusion of myocardial tissue following a period of ischemia. While perillaldehyde (PAE) has been suggested to have anti-inflammatory properties, its effects on MI/RI remain unclear. This study aimed to evaluate the impact of PAE on MI/RI injury. To simulate MI/RI in vivo, an ischemia-reperfusion (I/R) rat model was established. The levels of lactate dehydrogenase (LDH), creatine kinase (CK) and oxidative stress-related factors were measured using commercial assay kits. The myocardial infarct size was assessed through triphenyl tetrazolium chloride (TTC) staining. The expression levels of miR-133a-3p and inflammatory factors were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Myocardial cell apoptosis was evaluated by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining, and the protein levels of BCL2 associated X (Bax), BCL2 apoptosis regulator (Bcl-2) and mitogen-activated protein kinase 1 (MAPK1) were analyzed by Western blot. PAE could effectively alleviate MI/RI-induced myocardial injury by reducing the levels of LDH and CK, as well as decreasing infarct size. It also mitigated the myocardial inflammatory response by lowering the levels of proinflammatory factors. Additionally, PAE reduced oxidative stress and apoptosis in myocardial cells. Further experiments showed that these protective effects of PAE were associated with the up-regulation of miR-133a-3p, which in turn decreased MAPK1 levels. In conclusion, PAE attenuated MI/RI-induced myocardial injury, inflammatory response, oxidative stress and apoptosis in rats by inhibiting MAPK1, indicating that PAE may effectively reduce myocardial damage caused by I/R injury.

Perillaldehyde; Myocardial ischemia-reperfusion injury; Inflammation; Oxidative stress; Apoptosis; MAPK1

[1] Damluji AA, van Diepen S, Katz JN, Menon V, Tamis-Holland JE, Bakitas M, et al. Mechanical complications of acute myocardial infarction: a scientific statement from the American heart association. Circulation. 2021; 144: e16–e35.

[2] Kapur NK, Thayer KL, Zweck E. Cardiogenic shock in the setting of acute myocardial infarction. Methodist DeBakey Cardiovascular Journal. 2020; 16: 16–21.

[3] Dauerman HL, Ibanez B. The edge of time in acute myocardial infarction. Journal of the American College of Cardiology. 2021; 77: 1871–1874.

[4] Algoet M, Janssens S, Himmelreich U, Gsell W, Pusovnik M, Van den Eynde J, et al. Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends in Cardiovascular Medicine. 2023; 33: 357–366.

[5] Li H, Zheng F, Zhang Y, Sun J, Gao F, Shi G. Resveratrol, novel application by preconditioning to attenuate myocardial ischemia/reperfusion injury in mice through regulate AMPK pathway and autophagy level. Journal of Cellular and Molecular Medicine. 2022; 26: 4216–4229.

[6] Ahmed HM. Ethnomedicinal, phytochemical and pharmacological investigations of Perilla frutescens (L.) britt. Molecules. 2018; 24: 102.

[7] Erhunmwunsee F, Pan C, Yang K, Li Y, Liu M, Tian J. Recent development in biological activities and safety concerns of perillaldehyde from perilla plants: a review. Critical Reviews in Food Science and Nutrition. 2022; 62: 6328–6340.

[8] Zhang Y, Long Y, Yu S, Li D, Yang M, Guan Y, et al. Natural volatile oils derived from herbal medicines: a promising therapy way for treating depressive disorder. Pharmacological Research. 2021; 164: 105376.

[9] Zielinska-Blajet M, Pietrusiak P, Feder-Kubis J. Selected monocyclic monoterpenes and their derivatives as effective anticancer therapeutic agents. International Journal of Molecular Sciences. 2021; 22: 4763.

[10] Zhou F, Dai O, Peng C, Xiong L, Ao H, Liu F, et al. Pro-angiogenic effects of essential oil from Perilla frutescens and its main component (perillaldehyde) on zebrafish embryos and human umbilical vein endothelial cells. Drug Design, Development and Therapy. 2021; 15: 4985–4999.

[11] Yu L, Liu H. Perillaldehyde prevents the formations of atherosclerotic plaques through recoupling endothelial nitric oxide synthase. Journal of Cellular Biochemistry. 2018; 119: 10204–10215.

[12] Yin Y, Niu Q, Hou H, Que H, Mi S, Yang J, et al. PAE ameliorates doxorubicin-induced cardiotoxicity via suppressing NHE1 phosphorylation and stimulating PI3K/AKT phosphorylation. International Immunopharmacology. 2022; 113: 109274.

[13] Zhang L, Ding H, Zhang Y, Wang Y, Zhu W, Li P. Circulating microRNAs: biogenesis and clinical significance in acute myocardial infarction. Frontiers in Physiology. 2020; 11: 1088.

[14] Hepworth EMW, Hinton SD. Pseudophosphatases as regulators of MAPK signaling. International Journal of Molecular Sciences. 2021; 22: 12595.

[15] Gao T, Li J, Shi L, Hu B. Rosavin inhibits neutrophil extracellular traps formation to ameliorate sepsis-induced lung injury by regulating the MAPK pathway. Allergologia et Immunopathologia. 2023; 51: 46–54.

[16] Manríquez-Olmos L, Garrocho-Rangel A, Pozos-Guillén A, Ortiz-Magdaleno M, Escobar-García DM. Effect of tricalcium silicate cements in gene expression of COL1A1, MAPK’s, and NF-kB, and cell adhesion in primary teeth’ pulp fibroblasts. Journal of Clinical Pediatric Dentistry. 2022; 46: 17–24.

[17] Sun X, Zhang X, Yuan L, Zhang X, Fu Y. S100A7 promotes endometrial carcinoma progression by activating the MAPK signaling pathway. European Journal of Gynaecological Oncology. 2023; 44: 101–108.

[18] Wang Z, Luo W, Zhong P, Feng Y, Wang H. lncRNA HAGLR modulates myocardial ischemia-reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis. Open Medicine. 2022; 17: 1299–1307.

[19] Yu YN, Ren YY, Shao ZL, Chen BL, Cui BY, Chao CY, et al. Perillaldehyde improves diabetic cardiomyopathy by upregulating miR-133a-3p to regulate GSK-3β. European Journal of Pharmacology. 2023; 953: 175836.

[20] Frampton J, Ortengren AR, Zeitler EP. Arrhythmias after acute myocardial infarction. Yale Journal of Biology and Medicine. 2023; 96: 83–94.

[21] Zhang X, Zhao H, Horney J, Johnson N, Saad F, Haider KS, et al. Time-varying testosterone level and risk of myocardial infarction and stroke among hypogonadal men: a longitudinal study in Germany. Journal of Men’s Health. 2022; 18: 1–8.

[22] Moore A, Goerne H, Rajiah P, Tanabe Y, Saboo S, Abbara S. Acute myocardial infarct. Radiologic Clinics of North America. 2019; 57: 45–55.

[23] Zeymer U. Diagnosis and initial management of acute myocardial infarction. MMW—Fortschritte der Medizin. 2019; 161: 34–36.

[24] Saito Y, Oyama K, Tsujita K, Yasuda S, Kobayashi Y. Treatment strategies of acute myocardial infarction: updates on revascularization, pharmacological therapy, and beyond. Journal of the American College of Cardiology. 2023; 81: 168–178.

[25] Bae HE, Yoon Y-H, Kim J-Y, Cho Y-D, Choi S-H, Park S-J. Impact of COVID-19 outbreak on patients with ST-segment elevated myocardial infarction undergoing primary percutaneous coronary intervention in a regional emergency center in Seoul, Korea. Signa Vitae. 2023; 19: 165–172.

[26] Gulati R, Behfar A, Narula J, Kanwar A, Lerman A, Cooper L, et al. Acute myocardial infarction in young individuals. Mayo Clinic Proceedings. 2020; 95: 136–156.

[27] Tian H, Zhao X, Zhang Y, Xia Z. Abnormalities of glucose and lipid metabolism in myocardial ischemia-reperfusion injury. Biomedicine & Pharmacotherapy. 2023; 163: 114827.

[28] Wu D, Gu Y, Zhu D. Cardioprotective effects of hydrogen sulfide in attenuating myocardial ischemia‑reperfusion injury (Review). Molecular Medicine Reports. 2021; 24: 875.

[29] Valikeserlis I, Athanasiou AA, Stakos D. Cellular mechanisms and pathways in myocardial reperfusion injury. Coronary Artery Disease. 2021; 32: 567–577.

[30] Korshunova AY, Blagonravov ML, Neborak EV, Syatkin SP, Sklifasovskaya AP, Semyatov SM, et al. BCL2-regulated apoptotic process in myocardial ischemia-reperfusion injury (Review). International Journal of Molecular Medicine. 2021; 47: 23–36.

[31] Wang J, Wang H, Mou X, Luan M, Zhang X, He X, et al. The advances on the protective effects of ginsenosides on myocardial ischemia and ischemia-reperfusion injury. Mini-Reviews in Medicinal Chemistry. 2020; 20: 1610–1618.

[32] He J, Liu D, Zhao L, Zhou D, Rong J, Zhang L, et al. Myocardial ischemia/reperfusion injury: mechanisms of injury and implications for management (Review). Experimental and Therapeutic Medicine. 2022; 23: 430.

[33] Szunerits S, Mishyn V, Grabowska I, Boukherroub R. Electrochemical cardiovascular platforms: current state of the art and beyond. Biosensors and Bioelectronics. 2019; 131: 287–298.

[34] Zheng W, Liu B, Shi E. Perillaldehyde alleviates spinal cord ischemia-reperfusion injury via activating the Nrf2 pathway. Journal of Surgical Research. 2021; 268: 308–317.

[35] Xu L, Li Y, Fu Q, Ma S. Perillaldehyde attenuates cerebral ischemia-reperfusion injury-triggered overexpression of inflammatory cytokines via modulating Akt/JNK pathway in the rat brain cortex. Biochemical and Biophysical Research Communications. 2014; 454: 65–70.

[36] Lalem T, Devaux Y. Circulating microRNAs to predict heart failure after acute myocardial infarction in women. Clinical Biochemistry. 2019; 70: 1–7.

[37] Scarlatescu AI, Micheu MM, Popa-Fotea NM, Dorobantu M. MicroRNAs in acute ST elevation myocardial infarction—a new tool for diagnosis and prognosis: therapeutic implications. International Journal of Molecular Sciences. 2021; 22: 4799.

[38] Li S, Xiao FY, Shan PR, Su L, Chen DL, Ding JY, et al. Overexpression of microRNA-133a inhibits ischemia-reperfusion-induced cardiomyocyte apoptosis by targeting DAPK2. Journal of Human Genetics. 2015; 60: 709–716.