Nature’s Cure: The Impact of Medicinal Plants on Oxidative Stress and Inflammation in Cardiovascular Diseases

Cardiovascular disease (CVD) encompasses a range of conditions that affect the heart and blood vessels and is becoming increasingly prevalent worldwide. The rising incidence of CVD highlights the need for effective prevention and treatment strategies. Chronic illnesses, including CVD, are driven by various risk factors, with inflammation and oxidative stress playing key roles in disease progression (1). CVD is the world's biggest cause of death. More than 75% of deaths in low- and middle-income countries are caused by CVDs. In 2016, around 17.9 million deaths globally were attributed to CVDs, accounting for 31% of all fatalities. Eighty-five percent of these deaths were caused by heart attacks and strokes(2)Since the World Health Organisation (WHO) claims that over 75% of premature CVD cases are avoidable, improving the risk factors that are linked to CVD can significantly lessen the increasing burden of CVD on patients and healthcare providers(2). The World Health Organisation (WHO) states that over 75% of early CVD cases are preventable, hence reducing the associated risk factors can greatly lessen the growing burden of CVD on individuals and healthcare platforms(3).

One of the main causes of death worldwide is cardiovascular disease (CVD). Along with the rising rates of obesity, Type II diabetes, and hypertension, nations like India are having difficulty managing the impacts of CVD. Compared to Western countries, heart disease appears 10 to 15 years sooner in India(4). Hyperlipidaemia, which is caused by aberrant metabolism of fats, is a common cause of many long-term conditions, including cardiovascular disease (CVD). Cardiomyopathies, heart failure, heart attacks, coronary heart disease, hypertension, dyslipidaemia, and peripheral blood vessels disorders are all included in the category of heart disease (CVD). Around the world, CVD is the primary reason for both sickness as well as death. Cardiovascular disease currently accounts for more deaths among women than breast cancer. Among the nonmodifiable risk factors for cardiovascular problems, age and sex are most commonly cited. Heart-related diseases are more prevalent as people age. High blood pressure, elevated low-density lipoprotein, excessive alcohol intake, elevated psychological stress, cholesterol, inactivity, diabetes mellitus, abdominal obesity, and smoking are risk factors for cardiovascular disease(5). Inflammation of the arterial blood vessels is the primary cause of rheumatic heart condition, arterial thrombosis, pulmonary embolism, brain-vascular and peripheral arterial illnesses, and coronary heart disease (CHD).  A number of danger signs for cardiovascular diseases (CVDs) can be changed or avoided, such as poor eating habits, diets heavy in carbohydrates and low in protein, smoking, excessive alcohol use, diabetes mellitus, obesity and physical inactivity, high blood pressure, excessive consumption of red meat and saturated fats, sugary drinks, and excessive salt intake (6). Because endothelial cells' ability to suppress inflammation is diminished due to a decrease in nitric oxide (NO) availability, growth factors on the cell membrane and Chemoattractant can be produced by platelet activation, setting off a series of inflammatory reactions. Compounds with antioxidant and anti-inflammatory qualities, in addition to those that provide protection for the vascular endothelium, will be essential in the management of heart conditions. Medicinal plants include bioactive compounds that carry out these crucial functions(1) The risk of cardiovascular diseases (CVDs) and LDL cholesterol levels are strongly influenced by diet and lifestyle. Guidelines for Changes in lifestyle that lower fat and cholesterol intake, abstain from tobacco products, and maintain a healthy body mass index (BMI) through sufficient physical exercise should be given to those with CVDs. A BMI over 25 has been linked to a higher risk of CVDs, while a BMI below 20 is usually not advised. The lowest risk is seen in the 20–25 BMI range(1). 

Cardiovascular Diseases 

Acute myocardial dysfunction

In relation to COVID-19, the majority of commonly documented cardiovascular consequence is acute myocardial damage. Different definitions of acute myocardial damage have been used in different investigations. These definitions include abnormalities in the ECG and/or elevated cardiac enzyme levels (using different biomarkers and thresholds). Nonetheless, the most often recognised criterion is an increase in high sensitivity cardiac troponin I (cTnl) above the upper reference range of the 99th percentile. There has been variation in the total number of cases of acute heart damage; in about 8–12% of confirmed cases, there was a notable rise in cTnI levels (7). The previously published meta-analysis of the Chinese research revealed an 8% risk of acute heart injury(8), whereas a different study that only included patients with a clear result (either death or hospital discharge) revealed a 17% rate of cTnI elevation (9). Whether or not acute cardiac damage actually occurs, it has been repeatedly found to be a major poor forecast indication Among individuals with COVID-19,(9–11). Increased troponin levels are substantially more common in patients who are confined to the critical care unit or who suffer from serious or fatal illnesses. On the other hand, patients with minor diseases who do not require intensive care unit admission are very unlikely to have increased troponin levels (only 1-2%).

Arrhythmias
In COVID-19 patients, bradyarrhythmia and tachyarrhythmias are known to occur. As per study that examined the clinical features and results of 138 COVID-19 patients in China, the incidence of arrhythmia was 16.7% (11). At 44.4%, this incidence was far greater among patients hospitalised to the intensive care unit than it was among those who did not require ICU treatment, which was just 8.9%. It was unclear what kinds of arrhythmias were involved.

Hypertension

Over 20% of the general population suffers with hypertension, making it the most common ailment in developed nations. Despite the fact that numerous according to clinical research, decreasing blood although pressure lowers the risk of myocardial infraction and stroke, it significantly raises the risk of heart failure, stroke, myocardial infraction, and renal failure (12). Numerous environmental and genetic factors make it challenging to assess blood pressure fluctuations in the broader population. The study of uncommon Mendelian blood pressure variations, on the other hand, when major blood pressure extremes are caused by mutations in specific genes, has turned out to be quite educational. Gene mutations governing these pathways have been found in families with severe hypotension or hypertension. The autosomal dominant disorder called type II  pseudohypoaldosteronism is characterised by elevated salt reabsorption in the kidneys, hypertension, hyperkalaemia, and excretion of hydrogen and potassium ions. Wilson and associates discovered two genes that cause type II pseudohypoaldosteronism; these genes encode proteins that belong to serine-threonine kinases belonging to the WNK family. Intronic deletions on chromosome 12p are the cause of WNK1 mutations. Additionally, pseudo hypoaldosteronism type II is brought on by missense mutations in chromosome 17's hWNK4(12).

Antioxidant Medicinal Plants

Frequent aerobic metabolic processes, radiation exposure, redox cycling agents, and other environmental factors cause the body to produce radicals that are free. Reactive oxygen species (ROS) are created in vivo by the Oxygen is gradually reduced. These include hydrogen peroxide, superoxide anion, and hydroxyl radical. In addition to other ailments including diabetes and neurological disorders, research has indicated that ROS are important mediators in the development of cardiovascular illnesses. When free radical generation surpasses the antioxidant defence system's capabilities, Oxidative damage is the outcome of oxidative stress to macromolecules such proteins, lipids, and DNA. Glutathione peroxidase, superoxide dismutase, catalase, and decreased glutathione are among the enzymes that make up the human antioxidant defence system. Moreover, exogenous antioxidants such vitamin(1) Foods rich in flavonoids have been thoroughly examined and are known to be potent bioactive substances with a variety of biological effects that impact important signalling pathways of chronic diseases. It is well known that herbal preparations high in flavonoids can help manage metabolic disorders like diabetes mellitus and cardiovasculasr illnesses. It has been discovered that anthocyanins, such as cyanidin and delphinidin 3-glucoside, enhance insulin sensitivity, increase insulin secretion, and facilitate the liver's absorption of glucose in type 2 diabetes. By lowering triglycerides and dangerous fat accumulation, many flavonoids particularly flavanols are recognised for decrease blood pressure and preserve endothelial function Numerous flavonoid compounds have been discovered to offer a wide variety of therapeutic benefits in conditions of the heart, like heart-related disorders, endothelial dysfunction, cardiac fibrosis, myocardial infarction, and ischemic reperfusion injury(2). The body produces free radicals as an effect of regular aerobic metabolism and external influences including radiation and redox cycling materials. As oxygen is gradually reduced in vivo, reactive oxygen species (ROS) such as hydrogen peroxide, superoxide anion, and hydroxyl radical are produced. It has been observed that ROS play a key role as mediators in the emergence of cardiovascular condition as well as other illnesses like diabetes and neurological disorders. Oxidative stress is when the production of free radicals exceeds the antioxidant defence system's capacity, which leads to the progressive oxidation of large compounds like proteins, lipids, and DNA. Enzymes including reduced glutathione, catalase, superoxide dismutase, and glutathione peroxidase are part of the human antioxidant defence system. However, exogenous antioxidants such as ascorbic acid and vitamin E can improve the endogenous antioxidant system's efficacy(4). The ability of medicinal plants to protect against injury to smooth muscle cells in the arteries, endothelial cells, monocytes, cardiomyocytes, and macrophages has been demonstrated. The heart could be impacted by a quantity of chemicals, including diuretics, hypolipidemic, anticoagulants, antioxidants, and anti-inflammatory drugs. For instance, the main way that antioxidants prevent cardiovascular disease is by reducing the body's levels of free radical. Curry leaf is a plant that grows in East Asian countries that are tropical or subtropical, including China, India, Pakistan, and northeastern Australia. It is frequently used as flavouring in Indian cooking, especially in the southern regions. Many of curry leaf's bioactive components have potent antioxidant properties, and the leaf itself has a variety of therapeutic benefits. In diabetic mice, curry leaf is linked to a decrease in harmful LDL cholesterol and a rise in helpful HDL cholesterol, as well as a general decrease in total cholesterol and a drop in blood sugar levels. According to several studies, curry powder's antioxidant qualities reduced the early development of atheroma brought on by the oxidation of LDL cholesterol, implying a potential protection of cardiovascular disease (CVD) (6). Numerous types of medicinal plants, such as those with antiviral, anticancer, heat-clearing, and nourishing and tonic qualities, have had their antioxidant qualities evaluated in the literature (Cai et al., 2004; Chen et al., 2005; Li et al., 2008; Liu et al., 2008). However, the antioxidant qualities of a substantial class of Chinese medicinal herbs that are historically used as herbal tea to prevent and cure cardiovascular and cerebrovascular diseases have not been thoroughly examined (7). An efficient antihyperlipidemic drug is diosgenin. It promotes bone growth by dramatically boosting Type I collagen synthesis and secretion. Diosgenin may lessen the myocardial damage caused by isoproterenol, according to earlier research. By restoring the function of membrane-bound enzymes, its antioxidant qualities helped to maintain electrolyte balance, which may be the mechanism behind its cardioprotective effects(13). Glycyrrhizic acid has antioxidant qualities and protects against isoproterenol-induced cardiac injury, according to in vivo research. Vegetables including tomatoes, red carrots, watermelons, and papayas are rich sources of lycopene, a red carotenoid pigment. According to studies, lycopene is far more powerful than α-tocopherols at scavenging peroxyl radicals and quenching singlet oxygen than other carotenoids. Research has shown that lycopene protects against coronary artery disease, hyperlipidaemia, adrenaline-induced MI, and antioxidant activity(13). Endogenous antioxidant enzyme levels have been linked to cardiovascular disease, according to studies(14,15). In the development of cardiovascular illnesses, elevated ROS generation is frequently linked to increased lipid peroxidation, which damages arterial membranes. Since the production of ROS is essential to heart pathophysiology, treating oxidative stress may greatly improve the treatment of cardiovascular disorders. Additionally, because oxidative stress is a major contributing component, antioxidants may use a radical-scavenging method to reduce cellular damage and apoptosis(16). Myocardial dysfunction, for example, may be lessened by therapeutic strategies that either increase the function of natural antioxidant enzymes or decrease the formation of free radicals. The function of antioxidants in pharmacological studies is being studied in great detail. Because of their many health benefits, antioxidants have gained popularity recently. According to studies, they can lower the risk of heart disease(17). Plants contain chemicals known as antioxidants. Natural antioxidants have recently gained popularity on account of preventing cardiovascular problems such as ischaemia reperfusion (18). Terminalia arjuna a has been implicated in controlling the role of antioxidant enzymes in myocardial infarction caused by isoproterenol, according to studies by Jahan et al.(19). The researchers emphasised the polyphenol-rich T. arjuna extract's cardioprotective benefits in both therapeutic and preventative evaluations. The results show that the degree of isoproterenol-induced myocardial cell death was significant, as seen by the significantly increased levels of blood cardiac marker enzymes such LDH, AST and ALT. Increased lipid peroxidation may cause myocardial cell necrosis; however, the polyphenolic-rich extract's capacity to maintain membrane integrity and restrict enzyme leakage was demonstrated by the drop in serum levels of cardiac marker enzymes following delivery. In addition, T. arjuna therapy restored the magnitudes of myocardial antioxidant enzymes, such as SOD, CAT, and Peroxidase, which had been reduced by isoproterenol induction. When the effects of the plant extracts were compared to the combined effects of the common drugs gemfibrozil and propranolol, they were found to be similar. The extract's antioxidant qualities and polyphenolic components were credited by the researchers with the plant's possible advantages. It has been established that flavonoids have therapeutic potential for cardiovascular disease (CVD). Among the potential processes are their ability to limit platelet aggregation, reduce LDL oxidation, and ameliorate or avoid endothelial dysfunction (20). Studies have looked into Ocimum basilicum's possible heart health advantages. A member of the Lamiaceae family is O. basilicum. Significant terpenoids have been found in the essential oil that was taken from this plant, according to research. According to phytochemical investigations, steroids, polyphenols, and triterpenoids are present. The plant extract has beneficial effects on the changes in blood pressure observed in isoproterenol-induced cardiotoxicity, according to a study by Fathiazad et al.(21). The group's fibrosis and necrosis caused by isoproterenol are inhibited by the plant extract. Isoproterenol-induced myocardial necrosis has an acute phase that is linked to the production of toxic reactive oxygen species. According to reports, the integrity of the cardiac membrane was preserved. This integrity was assessed by measuring the degree of lipid peroxidation, specifically by looking at the concentrations of malondialdehyde (MDA) in serum and myocardial homogenates. The results showed that the extract significantly decreased the MDA levels that were raised by isoproterenol treatment. Ocimum basilicum's cardioprotective effects are ascribed to the flavonoids and phenolics in the plant's antioxidant qualities. These chemicals are found in high concentrations in plants that have the ability to scavenge radicals. The plant has a plasma lipid-lowering effect, which may be important for treating hyperlipidaemia and atherosclerosis, according to previous research by Harnafi et al. (22).

Fig : Mechanism of action of Medicinal Plant as Antioxidant in Cardiovascular Disease

Allium sativum, or garlic, has many health benefits that are associated with its antioxidant properties(23). In a several of models, garlic acid has been displayed to rise the generation of nitric oxide, which helps to avoid endothelial dysfunction(24–26). According to Shackebaei et al(27), garlic juice offers protection during reperfusion. The findings of this investigation demonstrated that garlic juice has an important vasodilatory effect upon the coronary arteries, increasing heart rate in the test group both prior to and throughout reperfusion. By releasing an intracellular enzyme marker, the authors also investigated the extent of reperfusion injury. Indicating considerable defence against malfunction of the endothelium and the inhibition of anaerobic metabolism inside the cardiac muscle cells, the test group was seen to have a lower level of lactate dehydrogenase (LDH) release. In instances of myocardial infarction brought on by isoproterenol, The ability to scavenge free radicals and act as an antioxidant the flavonoids and phenolic compounds found in Evolvulus alsinoides are associated with their cardioprotective advantages (28). The serum and heart tissue of the experimental animals showed near-normal levels of clinical marker enzyme activity, and there was a decrease in the release of enzymes from cardiac cell fractions, indicating a possible membrane stabilising effect (28) In conclusion, the antioxidant properties of flavonoids and phenolics that have been emphasised in a number of studies have helped to stabilise membranes, prevent platelet clumping, restore blood vessel function, lower lipid peroxidation, recover antioxidant enzymes, and suppress reactive oxygen species. Mohanty et al(1). The heart-protective qualities of Ocimum sanctum and Ginkgo biloba have also been mentioned in previous studies. Flavonoids and phenolics antioxidant qualities were connected to the cardioprotective effects of both plants. The study also linked these chemicals to the reduction of lipid peroxidation (29,30), the augmentation of reduced glutathione, and elevated levels of antioxidant enzymes. In rats with isoproterenol-induced myocardial necrosis, Panda and Naik (31) given a combination of Ginkgo biloba and Ocinum sanctum, confirming the heart-protective properties of certain substances that are bioactive found within the two therapeutic plants. This suggests a possible similarity to previously reported mechanisms, even though the combo treatment showed no discernible synergistic effect. Phenolics and flavonoids' strong capacity to scavenge free radicals is associated with their structure-activity connection. Free radicals can be scavenged by flavonoids due to the hydroxyl group's increased reactivity (31)

Anti-inflammatory role

When vascular tissues are exposed to damaging stimuli, inflammation is a complex biological reaction. It has a safeguard function as the body tries to get rid of bad things and start the healing process (32). Cells are activated and inflammatory mediators are released as part of the inflammatory response (33). Chronic heart failure and other cardiovascular disorders have been linked to the activation of inflammation (34,35), and its mediators might serve as important markers of the severity of the disease (36). Inflammatory responses in the artery wall are known to be triggered by markers such as cytokines and interleukins (37). Chemokines and leukocyte adhesion molecules are additional inflammatory agents (38). Leukocyte recruitment, adhesion, rolling, and endothelial cell activation, in addition to platelet adhesion and activation, are all signs of a reaction of inflammation within the microvasculature that can be brought on by risk factors like hypercholesterolaemia (39,40).  This can be avoided by having nitric oxide (NO) in the bloodstream. On the other hand, decreased NO availability results in vascular dysfunction and a decline in endothelial cells' anti-inflammatory capabilities(41). Wallace emphasised during his review the advantages of diets high in naturally occurring bioactive of diets rich in natural bioactive chemicals, particularly their ability to maintain and improve cardiovascular health. He discovered that flavonoids, a kind of polyphenol, are potentially effective preventative measures against cardiovascular disease (CVD) (42). The ability of many medicinal herbs to reduce inflammation has been documented. A review by Kadian and Parle (43) emphasised Ocimum sanctum's anti-inflammatory properties. The pharmacological efficacy of this plant, which has been recognised for its cardioprotective and antihypertensive properties, is ascribed to the suppression of certain inflammatory molecules (44). The linolenic acid found in Ocimum sanctum has anti-inflammatory properties, may be mediated via cyclooxygenase inhibition and lipoxygenase routes that are involved in the metabolism of arachidonate, according to Singh and Majumdar (45). The cyclooxygenase (COX) and lipoxygenase (LOX) enzymes are necessary for the production of lipid mediators from arachidonic acid, which are important in inflammation. According to Xing et al. (46), ginsenosides are triterpene saponins of the dammarane class that have anti-inflammatory qualities. Ophiopogonis Radix (the root of Ophiopogon japonicus (L.f) Ker-Gawl), Ginseng Radix Et Rhizoma Rubra (the root of Panax ginseng C.A. Mey.), and Schisandrae Chinensis Fructus (the fruit of Schisandra chinensis (Turcz.) Baill) were found to be able to lower the expression of inflammatory mediators. According to the study, one important bioactive ingredient that contributed to the noted anti-inflammatory benefits was ginsenosides. Blood artery dilatation, lipid peroxidation decrease, myocardial contractility, and anti-inflammatory properties were all found to be significantly enhanced by the three herbs in YQFM (47–50). A common contributing element to many illnesses, particularly cardiovascular diseases (CVDs), is inflammation. Although it hasn't been proven beyond a reasonable doubt that inflammation causes heart disease, those with CVD are known to have higher levels of inflammation. There is a clear correlation between increased inflammation and the risk of cardiovascular illnesses, according to a number of epidemiological and clinical research (51). Patients with CVD have been found to exhibit a range of inflammatory markers, elevated C-reactive protein sensitivity (CRP) being the most readily available and inflammatory marker with clinical reliability. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, another name for statins, are among the medications that have been found to reduce inflammation associated with cardiovascular disease (CVD) (52). Whether reducing C-reactive protein (CRP) actually lowers cardiovascular risk is unknown, though. Therefore, the need for safe and efficient medicines that can lower the risk of CVD is urgent. CVD may be less common and its risk factors may be reduced by the Lamiaceae family. It has been discovered that the aqueous extract of Ajuga iva, among other plants, has vasorelaxant properties in vitro. Nitric oxide (NO) modulation appears to have an impact on the vasorelaxation brought on by the Ajuga iva extract. NO plays a role in regulating the functional activity of macrophages and other inflammatory cell types. The inflammatory phospholipid mediator platelet-activating factor (PAF) has been demonstrated to be inhibited by derivatives of Lavandula angustifolia essential oils. This PAF suppression shields the heart muscle from metaproterenol induced myocardial infarction in rats (53). The ethyl acetate excerpt from L. Anguistifolia also inhibits iNOS/NO signalling, cyclooxygenase (COX)-2 gene expression, and IL1β, thereby reducing Inflammation caused by lipopolysaccharide (LPS) in RAW264.7 macrophages(54). Therefore, reducing CVD is aided by these plants' anti-inflammatory properties. Research has looked into Leonurus cardiac ability to fortify cardiac muscle, which could lower the risk of CVD (55). Extracts high in polyphenols from this plant are known to lower inflammation by preventing the release of PAF caused by staphylococcal peptidoglycan, even though the precise mechanism underlying muscular strengthening is unknown (56). Marrubium vulgare methanol extract has shown protective benefits against isoproterenol-induced acute myocardial infarction when given at 10, 20, and 40 mg/kg dosages (57). Furthermore, it has been demonstrated that an aqueous fraction of M. vulgare at a concentration of 40 μg/mL lessens Perfusion-ischemia (I/R) injury in rats (58). According to the findings, M. vulgare has heart-protective qualities. Because it prevents chemical that causes inflammation COX-2, it is possible that this property could be connected to its capacity to lower inflammation, even though the precise mechanism underlying its cardioprotective properties is still unknown. Used all over the world, Mentha arvensis has been shown to improve heart health by lowering inflammation. Significant reduction of IL-8 secretion in AGS cells was seen by an extract from this plant at a level of 100μg/ml, which may be related to cardiovascular disorders (CVD) (59). Additionally, M. piperita, another species of Mentha, has the ability to lower inflammation, both acute and long-term(60). Reduced levels Comprising fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), and tumour necrosis element-alpha (TNF-α) are associated with the anti-inflammatory effects (61). A reduction in CVD may be linked to M. piperita anti-inflammatory properties because those with CVD typically have higher levels of inflammation.  M. modarresi also has cardioprotective properties (62)RAW 264.7 in mouse macrophages, M. pulegium greatly reduced the release of IL-6, MCP-1, and TNF-α, proving its anti-inflammatory qualities (63). The idea that Lamiaceae can function as potent cardioprotective and anti-inflammatory medicines is supported by these studies.

Traditional medicine in several African countries has used Melissa officinalis as a calming agent, an antispasmodic, and for its cardioprotective qualities. This plant's essential oil showed anti-inflammatory qualities in tests Employing carrageenan and rats with injury to the hind paw oedema (64). Additionally, in rats, extracts from M. officinalis have demonstrated protective advantages against deadly ventricular arrhythmias brought on by reperfusion. Additionally, M. officinalis leaf lyophilised aqueous extract can be utilised to treat benign palpitations, which are a common problem that cause a lot of distress and make treatment more difficult. In a study, the frequency of heart palpitations decreased in healthy individuals who received 500 mg of freeze-dried M. officinalis leaf aqueous extract twice day for 14 days (or a placebo) (65). In a different randomised, double-blind clinical study, M. officinalis showed cardioprotective qualities through enhancing lipid levels, controlling blood sugar, and reducing inflammation (66). Additionally, Ocimum species extracts have a major impact on cardiac functioning. When rats were given isoproterenol, the ethanolic extract of the aerial portions of O. basilicum and O. sanctum prevented myocardial infarction (67)(68). The ability of Ocimum species to lower inflammation may be related to their cardioprotective qualities. Rat paw oedema caused by carrageenan and other inflammation mediators was shown to be alleviated by the essential oil of O. basilicum. Additionally, it prevented rats' metabolism of arachidonate, a major inflammatory mediator (69). In rats that had myocardial infarction brought on by isoproterenol, it was also discovered that the methanol extract from O. sanctum leaves decreased inflammation. 5-lipoxygenase, COX-2, leukotriene B4, and thromboxane B2 levels that were raised by isoproterenol were all reduced in rats that received this extract prior to treatment (70). Heart troubles are among the many health conditions that Origanum majorana has historically been used to treat. In rats that had myocardial infarction caused by isoproterenol, both powdered and aqueous extracts of sweet marjoram leaves increased corresponding weight of the heart, reduced the oxidative stress of the heart, and prevented the release of heart enzymes like aminotransferase, lactate dehydrogenase, and creatine phosphokinase(71). LPS-treated murine macrophage RAW264.7 cells showed an anti-inflammatory response to essential oil (EO) extracted from oregano leaves in in vitro tests. Additionally, this EO decreased the release and synthesis of TNF-α, IL-6, and interleukin (IL)-1β in RAW264.7 cells exposed to LPS (72). Oregano (Origanum vulgare) ethanol extract, in addition to its essential oil, also reduced inflammation caused by Propionibacterium acnes both in vitro and in vivo (73). Therefore, it is possible that the anti-inflammatory qualities of Origanum species Participate in their cardioprotective effects. Its potential for anti-inflammatory activities is shown by the fact that has been demonstrated that Plectranthus barbatus extract lowers the synthesis of pro-inflammatory cytokines. (74). Plectranthus species have also been shown to have anti-inflammatory qualities. Plectranthus amboinicus decreased the rise in the pro-inflammatory cytokines TNF-α and IL-8 in the blood in a model of rats that was generated by LPS (75). Activated human neutrophils' 5-lipoxygenase activity was markedly suppressed by Plectranthus zeylanicus extracts made with n-hexane or dichloromethane (76). The anti-inflammatory properties of Plectranthus species may aid in cardio protection, even if their cardioprotective advantages have not been well studied. Rosemary leaves are used to cure a variety of illnesses and have been shown in experiments to have anti-inflammatory qualities. By improving energy metabolism in a rat model, rosemary supplementation helped to decrease cardiac remodelling. When this supplement was taken after a myocardial infarction, diastolic function improved and hypertrophy decreased (77). An active ingredient found naturally in Leonurus cardiac, leu urine has demonstrated that provide a range of biological benefits, like as protection against cardiovascular diseases (CVDs). This substance acts as a supporting agent for heart protection and has been shown to lessen myocardial damage because of its antioxidant and anti-apoptotic characteristics. Leon urine also enhances anti-apoptotic gene expression Bcl-2 and suppresses the production of the pro-apoptotic protein Bax, which helps prevent acute myocardial ischaemia(78)(79). Apigenin, found in both L. cardiac and Apium graveolens, has shown similar methods of heart protection. By raising the protein Bcl-2 levels, lowering the expression of the Bax protein, and decreasing caspase-3 activity, it reduces cardiomyocyte apoptosis. Additionally, during cardiac ischemia/reperfusion (I/R), apigenin prevents p38 MAPKs from becoming phosphorylated. Leonurine inhibits cardiac cell death inside H9c2 cardiac cells by upregulating Akt phosphorylation, hypoxia inducible factor-1α (HIF-1α) expression, survivin, and VEGF (78).
Leonurine has also been demonstrated to lessen myocardial infarctions' severity and collagen deposition, prevent cell death, and enhance function of the heart. These consequences of leonurine were demonstrated to be handled by lower amounts of caspase3, cleaved-caspase3, and Bax, as well as elevated levels of Bcl-2, p-AKT, p-GSK3β, and phosphorylated (p)-PI3K. Thus, by triggering the activating PI3K/AKT/GSK3β signalling pathway, leonurine has strong cardioprotective and anti-apoptotic consequences (80). Rosmarinic acid has important cardioprotective qualities because it can increase the  antioxidant enzymes action and stimulate the way genes are expressed for rasoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and ryanodine receptor-2 (RyR2), both of which are essential for preserving Ca2+ balance (81). Rosmarinic acid protects the heart from fibrosis by activating AMPKα, reducing phosphorylation, and moving Smad3 to the nucleus, according to a new study. To lessen cardiac fibrosis, this substance also stimulates peroxisome proliferator-activated receptors (PPAR-γ) (82).

The activation of PPAR-γ also contributes to the cardioprotective effects of Apigenin, since its antagonist counteracted Apigenin's myocardial protective effects (83). Further studies showed that Apigenin reduced the cardiotoxicity caused by Adriamycin in mice and activated the Akt/PI3K/mTOR pathway (84)In vitro and in vivo, quercetin, a substance present in a number of plants in the Lamiaceae family, demonstrates notable cardioprotective effects. NF-κb, AP-1, and MMP-9 are among the inflammatory molecules whose expression is decreased by it (85). Quercetin also has cardioprotective qualities by inhibiting the actions of MAPK, JNK, and focal adhesion kinase in endothelial cells that are activated by thrombin (86). By increasing ATP levels, boosting antioxidant enzymes like GSH, and lowering elevated levels of cardiac TBARS, plasma creatine kinase, and NO(x), additionally, it has been discovered to as a cardioprotective substance (87,88). A naturally occurring bioactive substance, carvacrol, has cardioprotective qualities via a number of methods. By reducing the extent of the infarct and the levels of cardiac enzymes including cardiac troponin T, creatine kinase, and lactate dehydrogenase, studies have shown that it can reduce myocardial ischaemic damage in an acute myocardial infarction model in rats. It has also been discovered that carvacrol raises the activity of antioxidant enzymes such as glutathione, superoxide dismutase, and glutathione peroxidase while lowering malondialdehyde levels. Moreover, carvacrol has been demonstrated to upregulate the protein expression of Bcl-2 while simultaneously suppressing the activation of caspase-3 and BAX expression (89). Carvacrol showed anti-apoptotic qualities against rats cardiac I/R damage and raised the levels phosphorylated ERK, according to another study. Carvacrol also encouraged the Akt/eNOS pathway to be activated in cardiomyocytes, which led to cardio protection. Thus, carvacrol's cardioprotective advantages, linked to its anti-apoptotic and antioxidant properties, are mediated by MAPK/ERK and Akt/eNOS signalling pathways (90). One of Thymus species' main active compounds, thymoquinone, has been identified as potentially beneficial for cardiovascular health. Thymoquinone has been shown in a recent study to decrease the size of the infarct and enhance heart function. Rats suffering from cardiac ischemia/reperfusion damage, Thymoquinone's cardioprotective mechanism was associated with decreased cardiac levels of Lactate dehydrogenase, creatine kinase, and apoptosis inhibition (91).  According to research, it possesses antioxidative qualities by increasing the superoxide dismutase's function and reducing the production of malondialdehyde and hydrogen peroxide. Additionally, Thymoquinone increased SIRT1 expression and inhibited p53 acetylation, providing protection against heart injury(92). Scutellaria baicalensis, Scutellaria lateriflora, and other plants in the Lamiaceae family are the source of baicalein, an active chemical that exhibits heart-protective properties via a variety of molecular pathways. Apart from its anti-inflammatory qualities, it also has antioxidant capabilities. It has been demonstrated to lower MDA levels while increasing SOD and GSH-Px activity(93,94). It also prevents the NF-κB and MAPK pathways from being activated in rats. Additionally, this chemical showed the capacity to protect cardiomyocytes from cell oxidative stress-induced harm via the Nrf2/Keap1 pathway (95). The phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the expression of Na+/Ca2+-exchangers (NCX1) are also decreased by baicalein, although SERCA2 and RYR2 are increased (96).

Fig : Mechanism of action of Medicinal Plant as Anti-inflammatory in a Cardiovascular Disease

Table 1: Traditional and Modern Applications of Medicinal Plants in Cardiovascular Disease Treatment