Received 2022-07-31

Revised 2022-08-23

Accepted 2022-08-31

 Correspondence to: Mohsen Abbasnezhad, Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Telephone Number: +989144013766 Email Address: dr_nezhad@yahoo.com

Introduction

Cardiovascular diseases (CVDs) remain the most common non-communicable disease and the leading cause of mortality and disability worldwide, as per the world health organization, expected to cause more or less 23 million deaths by 2030 [1-4]. In addition to the high level of mortality rates, CVDs cause decrement in quality of life at the micro-level in patients and their families, as well as a result in a crucial financial burden on the health budget of countries, particularly those with low- and middle-incomes, at the macro-level [5-7]. Indeed, CVDs refer to all disorders related to the heart and blood vessels, including hypertension, atherosclerosis, cerebrovascular disease, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, cardiac arrhythmias, myocardial fibrosis, and heart diseases such as coronary heart disease, rheumatic and congenital heart disease, and cardiomyopathies [7, 8].

Significantly, in recent decades, both social changes (e.g., more sedentary jobs instead of physical demands, prolonged office work times, and decreased leisure and recreation time for frivolous accomplishments) and lifestyle changes (e.g., reduced physical activities, high fat and calories rich diets, smoking, and alcoholism) contributed to exponential development in CVDs cases [9-11]. CVDs risk factors are divided into two main categories, modifiable risks such as smoking, undesirable lipid profile, obesity, hyperglycemia, high blood pressure, prolonged stressful state, alcoholism, and reduced physical activities, and non-modifiable risks, including gender, age, and familial history [12-14].

Non-coding RNAs refer to a class of epigenetically functional RNAs, transcribed from DNA but translated into no proteins, including microRNAs (miRNAs), short interfering RNAs, PIWI-interacting RNAs, and long non-coding RNAs [15, 16]. Among them, miRNAs, a subclass of small non-coding RNA molecules, are made of approximately 22 nucleotides and modify gene expression negatively at the post-translational stage and positively in subcellular organelles like the mitochondria and nucleus [17, 18]. Many
recent studies determined the involvement of miRNAs in the pathogenesis of different types of CVDs, including hypertension, congenital heart disease, arrhythmia, diabetic cardiomyopathy, and heart failure. Therefore, miRNAs are considered novel biomarkers as well as therapeutic targets [9, 19-21]. Indeed, some evidence has demonstrated numerous signaling pathways involved in the underlying mechanisms of CVDs, in which miRNAs act as nodes of signaling networks that regulate the progression of CVDs [22, 23]. Despite the determination of the potential function of some miRNAs, most of the performed studies are preliminary; thereby, there is a significant absence of high-quality information and in-depth mechanistic insight into CVDs caused by altered miRNAs.

Over the past two decades, despite the remarkable advances in the treatment of CVDs, such as coronary artery disease and acute myocardial infarction, the mortality rate remains on the rise [24]. Nowadays, many studies have proposed novel pharmaceuticals and/or dietary antioxidants as a solution with minimal adverse effects for the treatment of various acute and chronic disorders such as cancer [25, 26], infertility [27-29], diabetes [30], endometriosis [31], viral infections [32], and
CVDs [33, 34]. Apigenin is one of the dietary flavonoids that, in addition to its favorite properties (such as anti-inflammatory, antioxidant, anti-tumor, and anti-apoptotic effects), represents the ability to prevent/alleviate CVDs by regulating the expression of miRNAs. Hence, the current review aims to provide information regarding apigenin role in relieving CVDs, and describe apigenin-induced mechanisms related to the modification of miRNAs expression.

Apigenin, a Widespread Flavonoid, Is
Capable of Alleviating CVDs Through Different Mechanisms

Flavonoids are a class of naturally-occurring phytochemicals with various functions abundantly found in almost all plant tissues. Basically, flavonoids are divided into different subclasses, such as flavones, flavans, flavonols, flavanones, flavan-3-ols, flavanonols, anthocyanidins, etc., based on their chemical structure [35, 36]. Overall, normalizing endothelial dysfunction, increasing vasodilation, and reducing oxidative stress are the main mechanisms by which these natural antioxidants exhibit their cardioprotective properties. Flavonoids could modify the endothelial nitric oxide synthase and sirtuin-1 pathways, for example, which are intracellular targets capable of maintaining the endothelial function by regulating miRNAs expression, suggesting that regulation of miRNAs by flavonoids is a promising approach to alleviate CVDs [37]. Furthermore, it is well established that the level of several miRNAs, such as miR-19b, miR-155, miR-146amiR-10b, miR-33a, miR-33b, and miR-378, along with the levels of ATP Binding Cassette Subfamily A Member 1 (ABCA1) and ABCG1, two major receptors involved in cholesterol metabolism, and expression of signaling pathways like nuclear factor-κB (NF-κB), nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, and PI3K/AKT could be modified by natural antioxidants leading to inhibition of atherosclerosis, a widespread fatal type of CVDs [38].

Apigenin (4′,5,7-trihydroxyflavone) is one of the most widespread flavonoids that belongs to the flavone sub-class [39]. The name of this dietary antioxidant is derived from the genus Apium. Dietary fruits and vegetables such as celery seeds, marjoram, Italian oregano, spinach, chamomile, parsley, sage, and pistachio are considered the enrichest sources of apigenin [39]. It is documented that the main sources of apigenin are the plants belonging to the Asteraceae family, such as those belonging to Artemisia, Matricaria, Achillea, and Tanacetum genera [40, 41]. Biogenetically, apigenin is produced by the phenylpropanoid pathway and can be obtained from both L-tyrosine and L-phenylalanine amino acids [42]. In this regard, both amino acids convert to p-coumaric acid but with different pathways. Upon the activation of p-coumaric acid with Coenzyme-A (CoA) and condensation with three residues of malonyl-CoA, the chalcone synthase enzyme performs the aromatization process to form chalcone. By the next stage, chalcone isomerase converts chalcone to naringenin, which is further oxidized by a flavanone synthase to form apigenin. Interestingly, apigenin is considered one of the most renowned nutraceuticals among all the phenolic compounds, which exerts countless nutritional and organoleptic properties [43, 44].

Like other flavonoids, apigenin and similar compounds such as naringenin, kaempferol, hesperidin, ellagic acid, and oleuropein can modulate the expression of miRNAs and also have cardioprotective properties [39]. Indeed, the large number of studies have claimed the palliative effects of apigenin on CVDs through the modification of various mechanisms. The peroxisome proliferator-activated receptor-γ (PPAR-γ) is one of the targets that apigenin could induce its activation results in the restoration of the left ventricular function, prevention of hemodynamic perturbations, and maintenance of the balanced redox status in the diabetic rat's myocardium; hence, protecting against myocardial infarction through attenuating edema, myonecrosis, apoptosis, and oxidative stress [45]. Similarly, Liu et al. demonstrated that the administration of apigenin alleviated diabetic cardiomyopathy via inhibition of cardiac remodeling, improvement of cardiac function, reducing cardiac interstitial fibrosis, suppression of cardiac oxidative stress, and prevention of cardiocytes apoptosis, all of which were caused by inhibition of NF-κB/p65 translocation and consequent inflammation [46]. In addition, Cardenas et al. suggested that the reduction in the activity of the NF-κB pathway, along with halting leukocyte infiltration and restoring normal metabolic function, are the main mechanisms by which dietary apigenin reveals its immune-regulatory properties [47]. Moreover, the downregulation of the NF-κB pathway is believed to contribute to the protection against abdominal aortic aneurysms, a multifactorial vascular disease caused by elastin degradation, chronic inflammation, and vascular smooth muscle cell phenotypic modulation through attenuation of pathological expansion of the aorta, preservation of the elastic fiber, and reduction in vascular inflammation [48].

In addition, excessive amounts of free fatty acids are acknowledged as the main cause of obesity and similar consequences such as hyperlipidemia, which in turn extensively disrupts the physiological function of vascular endothelium, the most immediately exposed tissue to the drastic effects of hyperlipidemia [49, 50]. More importantly, the dysfunction of the vascular endothelium is considered the initial step of CVDs in patients with obesity [51]. It is suggested by Miao et al. that apigenin is capable of protecting against lipotoxicity in human aortic endothelial cells via increasing cell viability, improving mitochondrial membrane potential, elevating nitric oxide production, and preserving proteomic content all of which through modification of regulatory pathways such as Foxo, inflammatory responses (including IL-17 and tumor necrosis factor), cell adhesion, and endoplasmic reticulum protein processing [52]. Furthermore, in human endothelial cells exposed to trimethylamine-n-oxide and the induced vascular inflammation, which is related to endothelial dysfunction, atherosclerosis, and elevated risk of CVDs, apigenin exerted alleviative effects on the expression of genes associated with arteriosclerosis, inflammasomes, and endothelial dysfunction including LOX-1, SR-PSOX, SREC, NLRP3, TXNIP, VCAM-1, ASC, ICAM-1, and MCP-1, as well as suppressed leukocyte adhesion and reduced the uptake levels of acetylated low-density lipoprotein [35]. So, it suggests that apigenin can retard vascular endothelium dysfunction by modifying the expression of scavenger receptors and uptake of the acetylated form of low-density lipoprotein, expression of adhesion molecules, and the formation of NLRP3 inflammasomes [53].

Apigenin Could Alleviate CVDs Through Modification of Regulatory miRNAs

Considering the current interest of researchers in determining and introducing miRNAs as the main factors involved in disease etiology, therapeutic targets, and diagnostic biomarkers in CVDs, several studies have investigated the possibility of modifying the expression of these regulatory molecules by apigenin, and as a result, prevention/alleviation of CVDs have been suggested. In the following, some miRNAs and its role were investigated.

miR-103

Several studies have suggested that miR-103 is involved in different types of CVDs. In atherosclerosis, Jiang et al. discovered that miR-103 contributes to the disease's progression as its inhibition is followed by attenuation in the inflammation and endoplasmic reticulum stress through disruption of the PTEN-mediated MAPK signaling pathway [54]. Furthermore, it is established that miR-103, along with miR107, targets Fas-associated protein with death domain (FADD) and thereby regulates programmed cardiac necrosis and myocardial ischemia/reperfusion injury [55]. Similarly, the inhibition of miR-103 resulted in the cardioprotection against myocardial infarction by affecting on FADD/RIPK pathway [56]. Cardiac hypertrophy is another CVD in which miR-103 is believed to be capable of affecting this disorder through the inactivation of autophagic flux via targeting TRPV3, a non-selective cationic channel [57]. Interestingly, Wang et al. [58] revealed that apigenin could attenuate the cardiomyocyte injury caused by myocardial infarction through the regulation of miR-103-1-5p. In this regard, the findings demonstrated that the administration of apigenin to mouse myocardial cells that underwent acute myocardial infarction was accompanied by downregulation of
miR-103-1-5p, which was followed by overexpression of Parkin, increment of the level of mitochondrial autophagy, and restoration of myocardial injury caused by hypoxia/reoxygenation [58].

miR-122-5p

In many studies, miR-122-5p has been related to different types of CVDs. Badacz et al. conducted a 6-year prospective evaluation of cardiovascular disease/ myocardial infarction/ ischemic stroke (CVD/MI/IS) in 142 patients with acute ischemia that was caused by carotid and/or coronary artery stenosis and these patients underwent revascularization for the symptomatic lesion [59]. The findings demonstrated that miR-122-5p was associated with peripheral artery disease, myocardial infarction, and creatine levels suggesting this miRNA is a potential risk factor for secondary cardiovascular events [59]. Furthermore, Šatrauskienė et al. described that
miR-122-5p is associated with metabolic syndrome-related subclinical aortic atherosclerosis [60]. In addition, miR-122-5p is reported to inhibit Hand2 and thereby be the inducer of mitochondria-dependent cardiomyocyte apoptosis and subsequent heart failure [61]. Moreover, the contribution of this miRNA to cardiovascular fibrosis and related diseases has been described
previously [62].

Interestingly, in 2021, researchers revealed that apigenin is able to enhance the expression of miR-122-5p, which is followed by overexpression of Smad7 and downregulation of HIF-1α, Smad2/3, p-Smad2/3, α-smooth muscle actin, and collagen I/III representing the functionality of apigenin in the treatment of cardiac fibrosis through the subsequent downregulation of HIF-1α expression and suppression of the collagen synthesis [63]. Concordantly, a most recent study described that apigenin regulates the expression of miR-122-5p and miR-155-5p, which the second one is discussed later, thereby alleviating myocardial fibrosis [63]. In this regard, the administration of apigenin resulted in the overexpression of miR-122-5p and downregulation of miR-155-5p that was followed by the downregulation of HIF-1α, upregulation of c-Ski, reduction in the levels of NF-κB/TGF-β1 signaling pathway, promotion of antioxidant ability, inhibition of TGF-β1-induced Smad2/3 expression, and overexpression of Smad7 [64].

miR-15b

It is documented that miR-15b, in a cascade involving MALAT1/miR-15b-5p/MAPK1, is able to alter the autophagic flux and the mTOR signaling pathway in endothelial progenitor cells; hence, affecting coronary atherosclerotic heart disease [65]. Moreover, the downregulation of miR15-b could leads to reduced incidence of arrhythmia, infarct size, and cardiomyocyte apoptosis along with suppressed inflammation and oxidative stress via by KNCJ2 overexpression [66]. According to the study conducted by Wang et al., the downregulation of miR-15b upon the administration of apigenin resulted in the overexpression of JAK2 and a higher activity of the JAK2-STAT3 pathway, disruption of myocardial apoptosis, and reduction of reactive oxygen species; hence, alleviation myocardial injury caused by ischemia/reperfusion [67].

miR-155

In accordance with other miRNAs, miR-155 has been associated with CVDs.
Faccini et al. reported that miR-155 is downregulated, suggesting this biomolecule is a novel biomarker for the diagnosis of coronary heart disease [68]. More importantly, the higher alteration in miR-155 expression, the more severe coronary heart disease [69]. Also, Ding et al. introduced miR-155, along with some other miRNAs, as a marker for screening of early heart failure diseases that was resulted by evaluating plasma levels in 62 subjects with heart failure [70].

It is reported that the administration of apigenin could alleviate myocardial fibrosis through the downregulation of miR-155-5p, which is accompanied by the overexpression of the c-Ski gene, and a significant downregulation in the levels of collagen I/III, α-smooth muscle actin, Smad2/3, and p-Smad2/3 representing the functionality of apigenin in the inhibition of cardiac fibroblast differentiation and extracellular matrix production via the regulation of miR-155-5p [71]. In addition, it is documented that the inhibition of miR-155-5p could assumed as novel therapy for lipopolysaccharide-induced cardiac apoptosis and septic myocardial
dysfunction [72]. Interestingly, apigenin can inhibit the lipopolysaccharide-induced miR-155 overexpression was followed by a significant increment in anti-inflammatory regulators such as FOXO3a and
SMAD2 [73]. However, its effectiveness in improving myocardial dysfunction caused by lipopolysaccharide has not been investigated.

miR-33

In concurrence with other mentioned micro-molecules, miR33 has been recommended as a possible biomarker in patients with coronary heart and artery diseases [74, 75]. In addition, Chen et al. reported that miR-33 can promote myocardial fibrosis via the inhibition of MMP16 and the stimulation of the
p38/MAPK signaling pathway [76]. Furthermore, it is documented that genetic ablation of miR-33 could disrupt physiological metabolism and elevate the risk of CVDs by increasing food intake and adipose tissue expansion, promoting obesity and insulin resistance [77]. Similarly, miR-33 is believed to be related to atherosclerotic plaques [78]. In this regard, it is documented that apigenin can suppress atherogenesis through the downregulation of miR-33, which results in the augmentation of ABCA1 expression, the enhancement of ABCA1-mediated cholesterol efflux, and the inhibition of inflammatory responses [79].

Conclusion

The findings of the current review study revealed that apigenin is capable of regulating different miRNAs, including miR-103, miR-122-5p, miR-15b, miR-155, and miR-33, which in turn modifies several signaling pathways, inhibits cardiac apoptosis, suppresses oxidative stress, alters autophagic flux, decreases coronary lipotoxicity and improve cholesterol efflux via affecting the expression of ABCA1. Also, it could considerate as a potential nutraceutical to prevent/alleviate different types of cardiovascular disorders.

Conflict of Interest

The authors declare that there is no conflict of interest.

References

1. Afzal M. Recent updates on novel therapeutic targets of cardiovascular diseases. Mol Cell Biochem. 2021;476(1):145-55.
2. Şahin B, İlgün G. Risk factors of deaths related to cardiovascular diseases in World Health Organization (WHO) member countries. Health Soc Care Community. 2022;30(1):73-80.
3. Rottapel RE, Hudson LB, Folta SC. Cardiovascular health and African-American women: A qualitative analysis. Am J Health Behav. 2021;45(4):735-45.
4. Bassey IE, Akpan UO, Nehemiah ED, Arekong R, Okonkwo OL, Udoh AE. Cardiovascular Disease Risk Factors and Cardiac Markers among Male Cement Workers in Calabar, Nigeria. Journal of Chemical Health Risks. 2017;7(2):85-94.
5. Kazibwe J, Tran PB, Annerstedt KS. The household financial burden of non-communicable diseases in low-and middle-income countries: a systematic review. Health Res Policy Syst. 2021;19(1):1-15.
6. Timmis A, Vardas P, Townsend N, Torbica A, Katus H, De Smedt D, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J. 2022;43(8):716-99.
7. Efremova O, Kamyshnikova L, Veysalov S, Sviridova M, Obolonkova N, Gayvoronskaya M, et al. Investigation on the Association of Cardiovascular Markers with Severity of Chronic Pyelonephritis. Arch Razi Inst. 2022;77(1):315-21.
8. Rezaei M, Sanagoo A, Jouybari L, Behnampoo N, Kavosi A. The effect of probiotic yogurt on blood glucose and cardiovascular biomarkers in patients with type II diabetes: a randomized controlled trial. Evid Based Care J. 2017;6(4):26-35.
9. Blaum C, Brunner FJ, Kröger F, Braetz J, Lorenz T, Goßling A, et al. Modifiable lifestyle risk factors and C-reactive protein in patients with coronary artery disease: Implications for an anti-inflammatory treatment target population. Eur J Prev Cardiol. 2021;28(2):152-8.
10. Mannoh I, Hussien M, Commodore-Mensah Y, Michos ED. Impact of social determinants of health on cardiovascular disease prevention. Curr Opin Cardiol. 2021;36(5):572-9.
11. Ndejjo R, Musinguzi G, Nuwaha F, Bastiaens H, Wanyenze RK. Understanding factors influencing uptake of healthy lifestyle practices among adults following a community cardiovascular disease prevention programme in Mukono and Buikwe districts in Uganda: A qualitative study. PLoS One. 2022;17(2):e0263867.
12. Elkoustaf RA, Nwaokoro M, Lahti DA, Yao JF, Gin N, Cotter TM, et al. Bridging the Gender Divide in Cardiovascular Rehabilitation: a Work in Progress. J Am Coll Cardiol. 2022;79(9_Supplement):1596.
13. Joseph P, Kutty VR, Mohan V, Kumar R, Mony P, Vijayakumar K, et al. Cardiovascular disease, mortality, and their associations with modifiable risk factors in a multi-national South Asia cohort: a PURE substudy. Eur Heart J. 2022;43(30):2831-40.
14. Pederiva C, Capra ME, Biasucci G, Banderali G, Fabrizi E, Gazzotti M, et al. Lipoprotein (a) and family history for cardiovascular disease in paediatric patients: A new frontier in cardiovascular risk stratification. Data from the LIPIGEN paediatric group. Atherosclerosis. 2022;349:233-9.
15. Andergassen D, Rinn JL. From genotype to phenotype: genetics of mammalian long non-coding RNAs in vivo. Nat Rev Genet. 2022;23(4):229-43.
16. Fang Y, Dai X. Emerging roles of extracellular non-coding RNAs in vascular diseases. J Cardiovasc Transl Res. 2022:1-8.
17. Tanase DM, Gosav EM, Petrov D, Teodorescu D-S, Buliga-Finis ON, Ouatu A, et al. MicroRNAs (miRNAs) in Cardiovascular Complications of Rheumatoid Arthritis (RA): What Is New? Int J Mol Sci. 2022;23(9):5254.
18. Wronska A. The role of microRNA in the Development, Diagnosis, and Treatment of Cardiovascular Disease-Recent Developments. Journal of Pharmacology and Experimental Therapeutics. 2022.
19. Altintaş N, Onur T, Yilmaz ÖS. Effects of microRNAs in hypertension disease. The Euro Res J. 2022;8(1):131-8.
20. Improta-Caria AC. Physical Exercise and MicroRNAs: Molecular Mechanisms in Hypertension and Myocardial Infarction. Arq Bras Cardiol. 2022;118:1147-9.
21. Li H, Chen M, Feng Q, Zhu L, Bai Z, Wang B, et al. MicroRNA‐34a in coronary heart disease: Correlation with disease risk, blood lipid, stenosis degree, inflammatory cytokines, and cell adhesion molecules. J Clin Lab Anal. 2022;36(1):e24138.
22. Li H, Zhan J, Chen C, Wang D. MicroRNAs in cardiovascular diseases. Med Review. 2022;2(9):140-68.
23. Santovito D, Weber C. Non-canonical features of microRNAs: Paradigms emerging from cardiovascular disease. Nat Rev Cardiol. 2022:1-19.
24. Jenča D, Melenovský V, Stehlik J, Staněk V, Kettner J, Kautzner J, et al. Heart failure after myocardial infarction: incidence and predictors. ESC Heart Failure. 2021;8(1):222-37.
25. Abbasi A, Movahedpour A, Amiri A, Najaf MS, Mostafavi-Pour Z. Darolutamide as a second-generation androgen receptor inhibitor in the treatment of prostate cancer. Curr Mol Med. 2021;21(4):332-46.
26. Samare-Najaf M, Samareh A, Jamali N, Abbasi A, Clark CC, Khorchani MJ, et al. Adverse Effects and Safety of Etirinotecan Pegol, a Novel Topoisomerase Inhibitor, in Cancer Treatment: A Systematic Review. Curr Cancer Ther Rev. 2021;17(3):234-43.
27. Jafari Khorchani M, Samare-Najaf M, Abbasi A, Vakili S, Zal F. Effects of quercetin, vitamin E, and estrogen on Metabolic-Related factors in uterus and serum of ovariectomized rat models. Gynecol Endocrinol. 2021;37(8):764-8.
28. Samare-Najaf M, Zal F, Safari S. Primary and secondary markers of doxorubicin-induced female infertility and the alleviative properties of quercetin and vitamin E in a rat model. Reprod Toxicol. 2020;96:316-26.
29. Samare-Najaf M, Zal F, Safari S, Koohpeyma F, Jamali N. Stereological and histopathological evaluation of doxorubicin-induced toxicity in female rats’ ovary and uterus and palliative effects of quercetin and vitamin E. Hum Exp Toxicol. 2020;39(12):1710-24.
30. Jamali N, Kazemi A, Saffari-Chaleshtori J, Samare-Najaf M, Mohammadi V, Clark CC. The effect of cinnamon supplementation on lipid profiles in patients with type 2 diabetes: A systematic review and meta-analysis of clinical trials. Complement Ther Med. 2020;55:102571.
31. Jamali N, Zal F, Mostafavi-Pour Z, Samare-Najaf M, Poordast T, Dehghanian A. Ameliorative effects of quercetin and metformin and their combination against experimental endometriosis in rats. Reprod Sci. 2021;28(3):683-92.
32. Jamali N, Soureshjani EH, Mobini G-R, Samare-Najaf M, Clark CC, Saffari-Chaleshtori J. Medicinal plant compounds as promising inhibitors of coronavirus (COVID-19) main protease: an in silico study. J Biomol Struct Dyn. 2021:1-12.
33. Da Purificação NRC, Garcia VB, Frez FCV, Sehaber CC, Lima KRDA, De Oliveira Lima MF, et al. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats. Biomed Pharmacother. 2022;151:113131.
34. Jamali N, Jalali M, Saffari-Chaleshtori J, Samare-Najaf M, Samareh A. Effect of cinnamon supplementation on blood pressure and anthropometric parameters in patients with type 2 diabetes: A systematic review and meta-analysis of clinical trials. Diabetes Metab Syndr. 2020;14(2):119-25.
35. Fan Z-k, Wang C, Yang T, Li X, Guo X, Li D. Flavonoid subclasses and CHD risk: a meta-analysis of prospective cohort studies. Br J Nutr. 2021:1-11.
36. Li Xq, Wang C, Yang T, Fan Zk, Guo Xf. A meta‐analysis of prospective cohort studies of flavonoid subclasses and stroke risk. Phytother Res. 2022;36(3):1103-14.
37. Lee Y, Im E. Regulation of miRNAs by natural antioxidants in cardiovascular diseases: Focus on SIRT1 and eNOS. Antioxidants. 2021;10(3):377.
38. Shao D, Lian Z, Di Y, Zhang L, Zhang Y, Kong J, et al. Dietary compounds have potential in controlling atherosclerosis by modulating macrophage cholesterol metabolism and inflammation via miRNA. npj Sci of Food. 2018;2(1):1-9.
39. Cannataro R, Fazio A, La Torre C, Caroleo MC, Cione E. Polyphenols in the Mediterranean diet: From dietary sources to microRNA modulation. Antioxidants. 2021;10(2):328.
40. Alrekabi DG, Hamad MN. Phytochemical investigation of Sonchus oleraceus (Family: Asteraceae) cultivated in Iraq, isolation and identification of quercetin and Apigenin. J Pharm Sci. 2018;10(9):2242-8.
41. Gao R, Lou Q, Hao L, Qi G, Tian Y, Pu X, et al. Comparative genomics reveal the convergent evolution of CYP82D and CYP706X members related to flavone biosynthesis in Lamiaceae and Asteraceae. PlJ. 2022;109(5):1305-18.
42. Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, et al. The therapeutic potential of Apigenin. Int J Mol Sci. 2019;20(6):1305.
43. Grumezescu AM, Holban AM. Therapeutic, probiotic, and unconventional foods. Elsevier; 2018.
44. Hostetler GL, Ralston RA, Schwartz SJ. Flavones: food sources, bioavailability, metabolism, and bioactivity. Adv Nutr. 2017;8(3):423-35.
45. Mahajan UB, Chandrayan G, Patil CR, Arya DS, Suchal K, Agrawal YO, et al. The protective effect of Apigenin on myocardial injury in diabetic rats mediating activation of the PPAR-γ pathway. Int J Mol Sci. 2017;18(4):756.
46. Liu H-J, Fan Y-L, Liao H-H, Liu Y, Chen S, Ma Z-G, et al. Apigenin alleviates STZ-induced diabetic cardiomyopathy. Mol Cell Biochem. 2017;428(1):9-21.
47. Cardenas H, Arango D, Nicholas C, Duarte S, Nuovo GJ, He W, et al. Dietary apigenin exerts immune-regulatory activity in vivo by reducing NF-κB activity, halting leukocyte infiltration and restoring normal metabolic function. Int J Mol Sci. 2016;17(3):323.
48. Li D, Ma J, Wang L, Xin S. Apigenin prevent abdominal aortic aneurysms formation by inhibiting the NF-κB signaling pathway. J Cardiovasc Pharmacol. 2020;75(3):229-39.
49. Ihm S-H, Park S-H, Lee J-O, Kim O-R, Park E-H, Kim K-R, et al. A Standardized Lindera obtusiloba Extract Improves Endothelial Dysfunction and Attenuates Plaque Development in Hyperlipidemic ApoE-Knockout Mice. Plants. 2021;10(11):2493.
50. Samsonov MV, Podkuychenko NV, Khapchaev AY, Efremov EE, Yanushevskaya EV, Vlasik TN, et al. AICAR Protects Vascular Endothelial Cells from Oxidative Injury Induced by the Long-Term Palmitate Excess. Int J Mol Sci. 2021;23(1):211.
51. Little PJ, Askew CD, Xu S, Kamato D. Endothelial dysfunction and cardiovascular disease: history and analysis of the clinical utility of the relationship. Biomedicines. 2021;9(6):699.
52. Miao X, Jin C, Zhong Y, Feng J, Yan C, Xia X, et al. Data-independent acquisition-based quantitative proteomic analysis reveals the protective effect of Apigenin on palmitate-induced lipotoxicity in human aortic endothelial cells. J. Agric. Food Chem. J Agr Food Chem. 2020;68(33):8836-46.
53. Yamagata K, Hashiguchi K, Yamamoto H, Tagami M. Dietary apigenin reduces induction of LOX-1 and NLRP3 expression, leukocyte adhesion, and acetylated low-density lipoprotein uptake in human endothelial cells exposed to trimethylamine-N-oxide. J Cardiovasc Pharmacol. 2019;74(6):558-65.
54. Jiang L, Qiao Y, Wang Z, Ma X, Wang H, Li J. Inhibition of microRNA‐103 attenuates inflammation and endoplasmic reticulum stress in atherosclerosis through disrupting the PTEN‐mediated MAPK signaling. J Cell Physiol. 2020;235(1):380-93.
55. Wang J-X, Zhang X-J, Li Q, Wang K, Wang Y, Jiao J-Q, et al. MicroRNA-103/107 regulate programmed necrosis and myocardial ischemia/reperfusion injury through targeting FADD. Circ Res. 2015;117(4):352-63.
56. Zaafan MA, Abdelhamid AM. The cardioprotective effect of microRNA-103 inhibitor against isoprenaline-induced myocardial infarction in mice through targeting FADD/RIPK pathway. Eur Rev Med Pharmacol Sci. 2021;25(2):837-44
57. Qi H, Ren J, E M, Zhang Q, Cao Y, Ba L, et al. MiR‐103 inhibiting cardiac hypertrophy through inactivation of myocardial cell autophagy via targeting TRPV 3 channel in rat hearts. J Cell Mol Med. 2019;23(3):1926-39.
58. Wang Z, Zhang H, Liu Z, Ma Z, An D, Xu D. Apigenin attenuates myocardial infarction-induced cardiomyocyte injury by modulating Parkin-mediated mitochondrial autophagy. J Biosci. 2020;45(1):1-9.
59. Badacz R, Kleczyński P, Legutko J, Żmudka K, Gacoń J, Przewłocki T, et al. Expression of miR-1-3p, miR-16-5p and miR-122-5p as possible risk factors of secondary cardiovascular events. Biomedicines. 2021;9(8):1055.
60. Šatrauskienė A, Navickas R, Laucevičius A, Krilavičius T, Užupytė R, Zdanytė M, et al. Mir-1, miR-122, miR-132, and miR-133 are related to subclinical aortic atherosclerosis associated with metabolic syndrome. Int J Environ Res. 2021;18(4):1483.
61. Shi Y, Zhang Z, Yin Q, Fu C, Barszczyk A, Zhang X, et al. Cardiac‐specific overexpression of miR‐122 induces mitochondria‐dependent cardiomyocyte apoptosis and promotes heart failure by inhibiting Hand2. J Cell Mol Med. 2021;25(11):5326-34.
62. Liu Y, Song J-W, Lin J-Y, Miao R, Zhong J-C. Roles of microRNA-122 in cardiovascular fibrosis and related diseases. Cardiovasc Toxicol. 2020;20(5):463-73.
63. Feng W, Ying Z, Ke F, Mei-Lin X. Apigenin suppresses TGF-β1-induced cardiac fibroblast differentiation and collagen synthesis through the downregulation of HIF-1α expression by miR-122-5p. Phytomedicine. 2021;83:153481.
64. Wang F, Zhang J, Niu G, Weng J, Zhang Q, Xie M, Li C, Sun K. Apigenin inhibits isoproterenol-induced myocardial fibrosis and Smad pathway in mice by regulating oxidative stress and miR-122-5p/155-5p expressions. Drug Dev Res. 2022;83(4):1003-15.
65. Zhu Y, Yang T, Duan J, Mu N, Zhang T. MALAT1/miR-15b-5p/MAPK1 mediates endothelial progenitor cells autophagy and affects coronary atherosclerotic heart disease via mTOR signaling pathway. Aging (Albany N Y). 2019;11(4):1089-109.
66. Niu S, Xu L, Yuan Y, Yang S, Ning H, Qin X, et al. Effect of down-regulated miR-15b-5p expression on arrhythmia and myocardial apoptosis after myocardial ischemia reperfusion injury in mice. Biochem Biophys Res Commun. 2020;530(1):54-9.
67. Wang P, Sun J, Lv S, Xie T, Wang X. Apigenin alleviates myocardial reperfusion injury in rats by downregulating miR-15b. Med Sci Monit. 2019;25:2764.
68. Faccini J, Ruidavets J-B, Cordelier P, Martins F, Maoret J-J, Bongard V, et al. Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease. Sci Rep. 2017;7(1):1-10.
69. Qiu X-K, Ma J. Alteration in microRNA-155 level correspond to severity of coronary heart disease. Scand J Clin Lab Invest. 2018;78(3):219-23.
70. Ding H, Wang Y, Hu L, Xue S, Wang Y, Zhang L, et al. Combined detection of miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 for screening of early heart failure diseases. Biosci Rep. 2020;40(3):BSR20191653.
71. Wang F, Fan K, Zhao Y, Xie M-L. Apigenin attenuates TGF-β1-stimulated cardiac fibroblast differentiation and extracellular matrix production by targeting miR-155-5p/c-Ski/Smad pathway. J Ethnopharmacol. 2021;265:113195.
72. Wang H, Bei Y, Huang P, Zhou Q, Shi J, Sun Q, et al. Inhibition of miR-155 protects against LPS-induced cardiac dysfunction and apoptosis in mice. Mol Ther Nucleic Acids. 2016;5:e374.
73. Arango D, Diosa‐Toro M, Rojas‐Hernandez LS, Cooperstone JL, Schwartz SJ, Mo X, et al. Dietary Apigenin reduces LPS‐induced expression of miR‐155 restoring immune balance during inflammation. Mol Nutr Food Res. 2015;59(4):763-72.
74. Reddy LL, Shah SA, Ponde CK, Rajani RM, Ashavaid TF. Circulating miRNA-33: a potential biomarker in patients with coronary artery disease. Biomarkers. 2019;24(1):36-42.
75. Xie Z, Ma P. MiR-33 may be a Biological Marker for Coronary Heart Disease. J Clin Lab. 2018;64(10):1755-60.
76. Chen Z, Ding H-S, Guo X, Shen J-J, Fan D, Huang Y, et al. MiR-33 promotes myocardial fibrosis by inhibiting MMP16 and stimulating p38 MAPK signaling. Oncotarget. 2018;9(31):22047.
77. Price NL, Singh AK, Rotllan N, Goedeke L, Wing A, Canfrán-Duque A, et al. Genetic ablation of miR-33 increases food intake, enhances adipose tissue expansion, and promotes obesity and insulin resistance. Cell Rep. 2018;22(8):2133-45.
78. Afonso MS, Sharma M, Schlegel M, Van Solingen C, Koelwyn GJ, Shanley LC, et al. miR-33 silencing reprograms the immune cell landscape in atherosclerotic plaques. Circ Res. 2021;128(8):1122-38.
79. Ren K, Jiang T, Zhou H-F, Liang Y, Zhao G-J. Apigenin retards atherogenesis by promoting ABCA1-mediated cholesterol efflux and suppressing inflammation. Cell Physiol Biochem. 2018;47(5):2170-84.