Review on the Cardioprotective Role of Pinocembrin in Atherosclerosis, Myocardial Infarction, and Associated Vascular-Myocardial Remodeling

Brindha E and Anupama BC

Published on: 2024-02-24

Abstract

Cardiovascular diseases represent a formidable global health challenge, standing as the foremost cause of both mortality and morbidity. Atherosclerosis and myocardial infarction, as primary contributors to this epidemiological burden, underscore the urgent need for effective therapeutic interventions with minimal side effects. Natural compounds derived from plants have emerged as promising candidates, given their enhanced efficacy and reduced adverse effects. Phytochemicals, in particular, have garnered attention for their potential as alternative therapeutic agents. This review delves into the cardioprotective potential of pinocembrin (5,7-Dihydroxy flavanone), a compound extracted from various plants and honey. Renowned for its antioxidant and anti-inflammatory properties, pinocembrin demonstrates significant cardioprotective effects through the modulation of diverse signaling pathways. Atherosclerosis and myocardial infarction entail intricate cellular mechanisms involving oxidative stress, inflammatory responses, cellular remodeling, and programmed cell death. Pinocembrin, by targeting key factors within these pathways, exhibits cardioprotective actions. While existing research underscores its effectiveness, further investigations are warranted to elucidate the impact of pinocembrin on additional cardiovascular conditions and explore novel molecular targets, thus paving the way for future advancements in therapeutic interventions.

Keywords

Pinocembrin; Atherosclerosis; MI; Cardioprotective Role

Introduction

According to data provided by the World Health Organization (WHO), cardiovascular diseases are the leading global cause of death, estimated at around 17.9 million deaths per year. Encompassing various clinical conditions affecting the heart and blood vessels, cardiovascular diseases result from a combination of modifiable and non-modifiable risk factors [1,2]. Common risk factors include smoking, alcoholism, metabolic disorders, and hypertension. While lifestyle modifications significantly reduce the incidence of these conditions, pharmaceutical therapies, particularly with advancing age, are often necessary [3].

However, prolonged use of synthetic drugs, such as widely used statins, may lead to undesirable side effects, particularly in patients with multiple medical co-morbidities [4]. This has spurred interest in researching the cardioprotective effects of plants and plant-derived compounds. Traditional folk medicines, with a history of treating various ailments, present a promising avenue for exploration, though a thorough evaluation of constituent phytochemical compositions and individual activities is essential.

Secondary plant metabolites, including phenolics, terpenes, flavonoids, alkaloids, and stilbenes, are produced in response to plant-environment interactions and serve as both regulatory and primary metabolites [5]. Due to their structural and chemical diversity, these phytochemicals offer potential health benefits and warrant investigation for their various therapeutic effects [6].

Among the well-studied plant secondary metabolites are flavonoids, which are abundant in plants and plant products. Possessing antioxidant, anti-inflammatory, antimicrobial, anticancer, and antidiabetic properties, flavonoids, including the natural compound pinocembrin, exhibit cardioprotective potential. This article focuses on exploring the cardioprotective effects demonstrated by pinocembrin in atherosclerosis, myocardial infarction, and associated vascular and myocardial remodeling.

Hypothesis

Pinocembrin is a primary flavonoid isolated from a variety of plants, including Pinus pinaster, Turnera diffusa, Alpinia mutica, Piper sarmentosum, Combretum collinum, Euphorbia hirta Linn, Dalia elegance, Alpinia galangal, Oxytropis falcate, Litchi sinensis, Lippia graveolens, Boesenbergia pandurata, Cryptocarya chinensis, Syzygium samarangense, Sparattosperma leucanthum, Alpinia pricei, Cleome droserifolia, Centaurea eryngioides, Cistus incanus, and Alpinia katsumadai [7]. Additionally, it can be obtained from propolis [8] and isolated from honey [9].

To enhance cost-effectiveness and yield, microbial biosynthesis from glucose molecules is a preferred method, involving genetically engineered bacteria [10,11]. Pinocembrin biosynthesis in E. coli can be achieved by inducing malonyl CoA production and reducing the accumulation of cinnamic acid [12,13].

Figure 1: Structure of Pinocembrin.

Pinocembrin can be used in the treatment of many diseases conditions as it shows antibacterial, anti-inflammatory, antimicrobial, anticancer, antifungal, neuroprotective activities [7]. It has anti- allergic [14] and anti-oxidant activities [8]. Safety and tolerability of pinocembrin administration in healthy subjects were studied and it was proven that 120mg single doses administered were tolerated with no clinically relevant changes [15].

Figure 2: Biological activities of pinocembrin.

Cardioprotective Role of Pinocembrin

Cardiovascular diseases, particularly atherosclerosis and myocardial infarction, arise from a variety of causes at the cellular level, including imbalances in cellular redox homeostasis, inflammatory responses, and cell death due to apoptosis and necrosis. Pinocembrin, with its antioxidant, anti-inflammatory, and anti-apoptotic activities, can thus be evaluated for its cardioprotective roles using in vitro and in vivo studies.

Action against Atherosclerosis

Atherosclerosis is one of the leading causes of death among cardiovascular diseases, and it is due to the increased lipid content developing into fat deposition in the intimal parts of the aorta and coronary arteries, limiting the blood flow to the heart muscles. This is a complex process initiated by the increased oxidation of low-density lipoprotein molecules, leading to the formation of oxidized LDL (oxLDL). Subsequently, these molecules are taken up by macrophages and converted into foam cells. Oxidative stress marks the risk factor for initiating these events. Subsequent changes are coordinated by the inflammatory and immune systems, leading to conditions of fibrosis. The atheromatous plaque grows as a result of fibrous cell proliferation, reducing arterial blood flow. Calcium ion deposition in this process makes the plaque hardened and results in thrombosis [16]. Increased production of reactive oxygen species (ROS), resulting in oxidative stress, is initiating this atherosclerotic process as well as mediating its progression, leading to adverse events [17]. One of the cellular protective mechanisms against oxidative stress is to activate the Nrf2/HO-1 signaling pathway [18].

Nrf2 is a transcriptional factor mainly involved in evoking the cellular antioxidant defense mechanism once activated by oxidative stress signals. In atherosclerosis, Nrf2 plays a dual role in defending against oxidative stress, and in adverse conditions of atherosclerosis, Nrf2 signals help in disease progression. But the main function of Nrf2 is to act as a key agent against oxidative stress-induced cellular damage. Oxidative stress is the major factor underlying cardiovascular diseases [19].

Nrf2 is seen in the cytoplasm associated with the regulatory protein KEAP-1 under normal redox conditions. But when the oxidant concentration starts to increase, the KEAP-1 protein changes its conformation and dissociates from Nrf2. Nrf2 can then translocate into the nucleus, where it binds with sMaf proteins to form heterodimers. This dimeric form can bind to specific regions of DNA through ARE (antioxidant response elements) and can transcribe a number of genes encoding antioxidant proteins like heme oxygenases-1 [20,21]. Heme oxygenases (HO) are intracellular microsomal enzymes that oxidize heme into biliverdin, carbon monoxide, and ferrous ions. Biliverdin then rapidly forms bilirubin by biliverdin reductase. All the products formed as a result of HO-1 action have antioxidant, anti-inflammatory, anti-apoptotic, and anti-thrombotic properties (Yoshimi Kishimoto, 2019; Jesus A. Araujo, 2012). Bilirubin is a potent antioxidant that scavenges peroxide radicals in vitro (Roland Stocker, 1987). CO is a vasoconstrictor (Morita, 2005), and the ferrous ion liberated by heme oxidation is immediately trapped by the protein ferritin, thereby reducing the free radical production induced by iron. HO-1 and ferritin are therefore co-expressed intracellularly (Sandra Fogg, 1999). The Nrf2/HO-1 pathway is considered the main pathway to defense against oxidative stress in pathological conditions [22,23]. The effect of pinocembrin on the Nrf2/ARE/HO-1 pathway was shown by its neuroprotective action in neuroblastoma SH-SY5Y cells by reducing injuries due to oxidative stress [24]. The antioxidant activity of pinocembrin can be attributed to its action on the Nrf2/ARE/HO-1 pathway (Zhi-Cong Zou, 2021) [25].

Doxorubicin, a drug widely used in the treatment of several human malignant conditions, exerts cardiac toxicity, mostly by triggering inflammatory responses and by inducing oxidative stress. The NF-kappa B/p38 MAPK signaling pathway plays a major role in inducing inflammatory responses due to doxorubicin-induced cytotoxicity [26]. In vitro studies on the effect of pinocembrin on doxorubin-induced cardiotoxicity using H9c2 cells showed that pinocembrin could reduce the cytotoxicity exerted by doxorubicin and could improve the cellular antioxidant system. Pinocembrin could improve mitochondrial function and reduce doxorubicin-mediated apoptosis [27] Pinocembrin, through the NF-kappa B/p38 MAPK pathway, helps in scavenging ROS production, thereby reducing ox-LDL-induced endothelial injury and reducing the atherogenic process [28].

Nrf2/HO-1 pathway induction may also ameliorate acute inflammatory responses involving cyclooxygenase action (COX) [29]. Cyclooxygenases are responsible for the biosynthesis of prostaglandins under acute inflammatory conditions. In vitro studies using pinocembrin showed its COX-1 and COX-2 inhibitory actions [30].

Action in Mental Infarction (MI)

The antioxidant role of pinocembrin in the ISO-induced MI rat model showed a significant rise in total antioxidant capacity by estimating reduced MDA, hydrogen peroxide, oxidized glutathione levels, increased superoxide dismutase activity, and circulating glutathione. NADH oxidase and NADPH oxidase activities were also lowered after treatment with pinocembrin, which were mostly contributing to the vascular oxidative stress level. This antiarrhythmic effect of pinocembrin was mediating through the Nrf2/HO-1 signaling pathway, as indicated by both of these parameters at elevated levels [31,32].

Myocardial infarction indicates myocardial necrosis due to prolonged ischemia [3]. Acute myocardial infarction denotes an infarction less than 3-5 days old and an irreversible necrosis of myocardium > 1cm, and it usually happens because of clot formation or atherosclerotic plaque formation within the arteries. But generally, acute myocardial infarction depends on the supply of oxygen to the muscle cells and the oxygen demand of these cells. When there is too much oxygen demand, as in an increased heart rate, or less oxygen supply to the cells due to low blood pressure, myocardial cell damage can happen without any such blood flow obstructions [34,35]. Prolonged myocardial ischemia brings a lot of biochemical changes to the affected cardiomyocytes. Lack of oxygen leads to metabolic alterations, switching on anaerobic metabolic pathways. Lactate produced as a result of anerobic glycolysis results in a fall in intracellular pH, and to balance this, the Na+-H+ exchanger gets activated to eliminate the excess proton produced, further leading to intracellular sodium overload. When oxygen supply is reduced, the oxidative phosphorylation reaction stops, leading to depolarization of the mitochondrial membrane, and ATP scarcity limits Na+-K+ ATPase functioning, resulting in sodium overload. Triggering the action of the Na+-Ca2+ exchanger to balance the intracellular sodium level builds up intracellular Ca2+ overload [36]. These metabolic changes, along with oxidative stress and inflammatory and immune reactions within cardiomyocytes, bring irreversible changes to these cells, which later on affect the thickness of the entire ventricular wall. So, the repair mechanism triggered by cytokines and inflammatory chemokines builds up a collagen-based scar in the affected area to prevent cardiac rupture, ultimately leading to the ventricular remodeling process [37].

Post-infarct remodeling is mainly initiated by the TGF-β superfamily cytokines, especially TGF-β1, released by cardiomyocytes, macrophages, endothelial cells, etc. in response to redox imbalance. The signal cascade starts when TGF-β1 binds with its receptor, TGF-β1RII, which then phosphorylates TGF-β1RI, and this dimerized receptor-ligand complex can further phosphorylate and start intracellular signaling pathways, of which the SMAD superfamily plays the major role. Smad 2/3 gets phosphorylated at first, and then it binds with Smad4 to form a heterodimer, which in turn can translocate into the nucleus. TGF-β1-induced Smad signaling can then induce or repress DNA transcription within the nucleus, giving rise to several inflammatory and immune components required for myocardial fibrosis and remodeling [38]. The anti-inflammatory and antioxidant properties of pinocembrin play together in producing an antifibrotic effect in the liver through TGF-β/Smad signaling pathway inhibition and by reducing proinflammatory cytokine production [39]. Pinocembrin has also been shown to alleviate ventricular arrythmia in I/R rat models through Na+-K+ ATPase and Ca2+-Mg2+ ATPase activity enhancements [40]. It has also been shown to ameliorate MI-induced atrial arrythmias by suppressing inflammatory responses and decreasing atrial remodeling, atrial fibrosis, atrial electrical remodeling, etc. [41]. Pinocembrin has been shown to upregulate anti-apoptotic protein bcl-2 expression and downregulate the expression of pro-apoptotic proteins like p53, bax, and cleave caspases. The p53 protein downregulation by pinocembrin also plays a role in restoring the altered function and distribution of VEGFR2 by attenuating the anti-angiogenesis effect of p53 by inhibiting hypoxia-inducible factor-1α (HIF-1α). The post-MI ventricular remodeling was attenuated by decreasing collagen fiber deposition by approximately two folds in the untreated condition and by exerting antioxidant effects through Nrf2/HO-1 pathway activation. Therefore, the anti-apoptotic, anti-fibrotic, and angiogenesis effects of pinocembrin help prevent tissue remodeling in post-MI [42].

In vivo studies on ischemia-reperfusion (I/R) injury in rats showed that pinocembrin could protect the heart from acute myocardial infarction I/R injury and improve post-ischemic cardiac function. This protective effect of pinocembrin is achieved by enhancing glycolysis in cardiomyocytes and through the activation of PFKFB3. The reduced glycolysis in myocardial infarction I/R injury can be compensated through pinocembrin administration, as the result of this glucose oxidation increases, PFKFB3 gets upregulated, and cellular glucose from PPP redirects to glycolytic pathways by upregulating the expression of the key transcription factor H1F1α [43]. When studying I/R in Wistar rat models, pinocembrin-treated animals showed improved MDA levels and a decreased Bax/Bcl2 ratio. Infarcted issues showed an increase in the ratio of phosphorylated connexin43 to total connexin43, showing improved cardiac function in pinocembrin-treated animals. Pinocembrin can elevate the phosphorylation of connexin43 in ischemic myocardium and can also reduce arrythmias [44]. Pinocembrin also exerts a protective effect on cerebral ischemic injury in rat models [45].

Anxiety and depression in patients during the postoperative period were found to be closely associated with atrial fibrillation (AF) [46]. The effect of pinocembrin on atrial fibrillation induced by depression was studied in rodent and rat models, and it clearly showed multiple therapeutic effects of using this compound in ameliorating the AF susceptibility in depressed rats by reducing oxidative stress, atrial βchannels, and gap junctions [31,47].

Figure 3: Antioxidant, anti-inflammatory, antiapoptotic and antifibrotic effect of pinocembrin in cardioprotective action.

Action in Cardiac Hypertrophy

When the heart is subjected to an increased workload, the compensatory mechanism employed by the organ to adapt to this situation results in cardiac hypertrophy [48]. Angiotensin II action triggers the Rho A signaling pathway, leading to a cardiac hypertrophic condition. ROCK is therefore targeted at ameliorating cardiac hypertrophy, cardiac remodeling, and oxidative stress by suppressing endothelial nitric oxide synthase expression. RhoA, a GTP-binding protein, through its Rho-associated kinase (ROCK) pathway controls the cardiovascular system by regulating cellular motility, adhesion, proliferation, migration, and apoptosis. When bound with GDP, Rho A will be in the inactive form, and replacing GDP with GTP makes Rho A into an active state. GTP-bound Rho A then binds with ROCK, making the latter into an active state. The Rho A/ROCK pathway upregulates VCAM-1 and ICAM-1 expression on endothelial cells, inducing inflammatory responses and leukocyte infiltration [49]. Pinocembrin has been shown to block this Rho A/ROCK pathway in angiotensin II-induced aortic constriction rat models [50]. Pinocembrin also suppresses the expression of pro-inflammatory vascular adhesion molecules (ICAM-1, VCAM-1, and E-selectin) through its anti-inflammatory effects [28].

Vasorelaxant injury is one of the main issues in developing cardiovascular diseases, mainly mediated through the endothelium-dependent NO/cGMP signaling pathway [51]. The vasodilation process also relies on endothelium-independent mechanisms involving Ca2+ and K+ channels [52]. Pinocembrin induces aortic ring relaxation in rats either through endothelium-dependent pathways or endothelium-independent pathways [53].

Conclusion

primarily through its antioxidant, anti-inflammatory, anti-apoptotic, vasodilatory, and antifibrotic effects, even though there are not many studies done on its cardioprotective action. Since the compound has shown therapeutic effects through regulating different signaling pathways, more studies on cardiomyocytes should be done to elucidate its potent effect as a cardio-protecting agent. This review suggests more in vitro and in vivo studies using pinocembrin in different cardiovascular disease conditions.

Global Journal of Applied Sciences and Technology