Role of Marine Drugs in Cardiovascular Diseases Management: History
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Cardiovascular diseases (CVDs) are among the most impactful illnesses globally. The available therapeutic option has several side effects, including hypotension, bradycardia, arrhythmia, and alteration in different ion concentrations. Recently, bioactive compounds from natural sources, including plants, microorganisms, and marine creatures, have gained a lot of interest. Marine sources serve as reservoirs for new bioactive metabolites with various pharmacological activities. The marine-derived compound such as omega-3 acid ethyl esters, xyloketal B, asperlin, and saringosterol showed promising results in several CVDs. 

  • marine drugs
  • cardiovascular diseases
  • atherosclerosis

1. Hypertension

Hypertension is one of the most severe problems among all cardiovascular diseases (CVDs), and is responsible for stroke, ischemic heart disease, dementia, chronic kidney disease, and other CVDs [1]. According to 2019 age-standardized prevalence data, 32% of women and 34% of men aged 30–79 worldwide had hypertension [2]. Many marine natural compounds, including bioactive molecules, chito-oligosaccharide derivatives (COS), and phlorotannins, were obtained from marine species and are potential leads for ACE inhibitors and evolved as nutraceutical medicinal compounds for the treatment of hypertension [3][4]. Natural marine ACE inhibitors are being studied as alternatives to synthetic drugs to avoid several serious side effects and hold a significant potential to become new therapeutic options for the treatment of hypertension [5]. Biopeptides or ACE-inhibitory peptides derived from fish proteins are often made under controlled circumstances by proteolyzing marine proteins advanced for the treatment of hypertension [6]. Furthermore, marine red algae Gracilariopsis lemaneiformis have been identified as producing several marine-based new ACE inhibiting peptides, FQIN [M(O)] CILR and TGAPCR, discovered by LC-MS/MS screening in G. lemaneiformis protein hydrolysates. These peptides significantly decreased systolic and diastolic blood pressure (DBP) in the spontaneously hypertensive rat model [7]. In the same direction, Sato M. et al. identified seven peptides: Val-Tyr, Ile-Tyr, Ala-Trp, Phe-Tyr, Val-Trp, Ile-Trp, and Leu-Trp from hydrolysates of wakame (Undaria pinnatifida) brown seaweed using three steps, HPLC and liquid chromatography-mass spectroscopy. Four of seven seaweed-derived peptides (Val-Tyr, Ile-Tyr, Phe-Tyr, and Ile-Trp) significantly reduced systolic blood pressure in spontaneously hypertensive rats at a dose of 1 mg/kg. This offers a possible source of new AEC inhibitors as antihypertensives [8]. In addition, Sun et al. also identified two Phe-Gly-Met-Pro-Leu-Asp-Arg (FGMPLDR; MW 834.41 Da) and Met-Glu-Leu-Val-Leu-Arg (MELVLR; MW 759.43 Da) ACE inhibitory peptides from the protein hydrolysate marine macroalga of Ulva intestinalis. In silico and in vitro molecular docking studies revealed these two peptides have ACE binding and inhibitory activity [9].
One of the most well-known marine-derived compounds is alginate oligosaccharides (AOS) that offer protection against perivascular inflammation, reduction in the vascular luminal area, and hemodynamic alterations of pulmonary hypertension in the rat produced by monocrotaline (MCT) model via downregulating P-selectin [10]. Another study demonstrated that omega-3 Q10, a polyunsaturated fatty acid (n3-PUFA) formulation, appears to be more effective than soybean oil supplementation at reducing diastolic blood pressure and associated symptoms with hypertension in older adults [11]. Moreover, mangrove fungus-isolated xyloketal B showed phenylephrine (Phe)-induced contractions induced hypertension protection by decreasing the systolic and diastolic blood pressure via enhancing endothelial NO release through the Akt/eNOS pathway [12]. In addition, a controlled trial study conducted by Sámano MJ et al. evaluated the combination of Spirulina (Arthrospira) maxima (filamentous, gram-negative cyanobacterium) with angiotensin-converting enzyme (ACE) inhibitors in patients with systemic arterial hypertension (SAH) and accessed its effects on endothelial damage and oxidative stress. Results showed that Spirulina significantly reduced systolic blood pressure, increased anti-oxidant level (glutathione peroxidase activity and oxidized glutathione), and decreased endothelial damage markers (sVCAM-1, sE-selectin, and endothelin-1) [13]. It has other properties such as antiviral, anti-dyslipidemic, and antioxidant [14]. Low molecular mass potassium alginate (L-PA), brown algae, shows an antihypertensive effect on DOCA salt-induced hypertension in rats (Figure 1) [15]. Overall, data suggested that marine-derived compounds have the potential to cure hypertension, but a detailed mechanistic study is still needed. Moreover, Therapeutic potential of marine drugs in CVDs management has been tubulated in Table 1.
Figure 1. Possible mechanism of different marine-derived compounds in CVDs.
Table 1. Preclinical study of marine drugs in various CVDs.

2. Atherosclerosis

Atherosclerosis is a chronic, inflammatory, progressive cardiovascular disease that results from ongoing blood vessel damage brought on by hyperlipidemia and increased cholesterol levels [33]. Marine-based derived compounds have been effective against atherosclerosis since ancient times. These compounds have advantages over synthetic compounds in atherosclerosis due to greater effectiveness and lower side effects [34]. Marine-derived algal polysaccharides are the active ingredients in products made from marine sources that have a hypolipidemic impact and cure atherosclerosis.
Saringosterol, a phytosterol derived from the edible marine seaweed Sargassum fusiforme, has high and selective liver X receptor (LXR) activity [35]. Yan et. al. reported that saringosterol treatment reduced the burden of atherosclerotic plaques while having no negative effects on the liver of apoE-deficient rats. Saringosterol reduces cholesterol homeostasis disruption, influencing atherosclerosis’s progression [19]. However, asperlin is derived from the marine fungus Aspergillus versicolor LZD4403 and possesses antifungal and anti-inflammatory properties. Zhou Y et. al. reported that asperlin has atheroprotective potential in vitro and in vivo. Results indicated that asperlin treatment significantly reduced inflammatory cytokines (iNOS, IL-1β, and TNF-α), increased protective cytokines (IL-10 and IL-4), and reduced aortic dilation and atherosclerosis plaque formation in the aorta [17]. This suggested that the anti-inflammatory properties of asperlin could be beneficial against atherosclerosis. Manzamine A is a naturally occurring alkaloid obtained from the sea sponge Acanthostrongylophora ingens [36]. In atherosclerosis, Eguchi et al. conducted a study where Manzamine A suppressed acyl-CoA: cholesterol acyl-transferase activity in hamster ovary cells. In addition, Manzamine A treatment significantly reduced the serum level of total cholesterol, free cholesterol, LDL-cholesterol, triglyceride, and atherosclerotic lesion formation in apolipoprotein E (apoE)-deficient mice [20]. Astaxanthin is a xanthophyll pigment obtained from microalgae, fungi, complex plants, seafood, and flamingos. As an antioxidant with anti-inflammatory characteristics, it has the potential to be used as a treatment for atherosclerotic cardiovascular disease [37]. Yang Y et. al. demonstrated the hypocholesterolemic effect of astaxanthin via reducing total plasma cholesterol, TG and increased LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl CoA reductase, and sterol regulatory element binding-protein 2 (SREBP-2) and greater mature SREBP-2 protein apoE(-/-) mice (Figure 2) [21]. In high-fat diet mice, Xyloketal B also protects against atherosclerosis through a strong antioxidant effect [18].
Figure 2. Mechanisms of Manzamine A, Astaxanthin, and Asperlin in CVDs.
Moreover, there are several major causes of atherosclerosis. However, thermo-inflmation plays a crucial role in atherosclerosis pathogenesis via influencing the plague formation. Thrombo-inflammation refers to the complex cascading interaction between the blood coagulation process and inflammation in the pathogenesis of CVDs [38]. The formation of arterial thrombosis is mostly caused by platelet adhesion under high shear stress, which arises in stenotic atherosclerotic arteries [39]. Meanwhile, platelet-activating factor (PAF) is a powerful lipid mediator that acts through PAF/PAF-R pathways and is a key player in inflammation by recruiting neutrophils and activating platelets in the development of atherosclerosis [40].
Several marine-derived drugs have been investigated to inhibit thrombo-inflammation in CVDs. Fascaplysin is a Fijian marine sponge derived from the genus Fascaplysinopsis [41], which is a kinase inhibitor with anti-thrombotic properties via inhibiting GPIIb/IIIa activation, platelet aggregation, and thrombus formation [23]. Another cyclodepsipeptide marine compound Isaridin E derived from the Amphichorda feline (Beauveria feline) fungus [42], demonstrated the dose-dependent inhibition of platelet activation, aggregation, and secretion. However, it does not have any effect against thrombin- or collagen-induced platelet aggregation. Isaridin E also showed an antithrombotic effect without increasing bleeding time in a dose-dependent manner against the FeCl3-induced carotid mouse model [24]. F-fucoidan (FD) is a polysaccharide compound derived from the brown alga Laminaria japonica that also shows an antithrombotic effect through shortening the blood lysis time, H2O2 expression stimulation, and H2O2 released after induction of PGI2 production and might be effective in CVDs’ patients [43]. The anti-thrombotic and anti-atherosclerotic properties of marine-derived omega 3 polyunsaturated fatty acids (n-3 PUFA) may help to reduce heart failure by lowering the risk of ischemic heart disease. It is known that n-3 PUFA enhances plasminogen activator inhibitor-1 by lowering fibrinogen and decreasing platelet-derived thromboxane A2 (TXA2), which increases platelet aggregation and vasoconstriction [44]. Therefore, So, overall, it seems like marine-based drugs could be used to treat atherosclerosis, but a more detailed mechanistic study is still needed.

3. Myocardial Infarction (MI)

MI occurs due to the occlusion of the coronary artery, leads to a shortage in oxygen and nutrients, and causes irreversible necrosis and death of cardiomyocytes [45]. It is the major cause of death and disability among other CVDs worldwide [46]. Using marine-derived metal nanoparticles, a novel method for treating thrombus dissolution and myocyte healing in infarcted areas (myocardial infarction) [47]. The anti-myocardial infarction activity of the gold nanoparticles (GNPs) was an innovative method in which cyanobacterial extract, GNP solution, and a combination of both were developed [25]. Omega-3 polyunsaturated fatty acids (PUFA), a marine compound, have shown beneficial benefits on myocardial infarction by reducing MI size in experimental and clinical research (Figure 2) [44]. Docosahexaenoic acid (DHA) is a long-chain omega-3 PUFA obtained from the marine source that has shown a protective effect against myocardial infarction [27]. An in vivo study of DHA in a rat model showed a protective effect against MI at 5 g/kg [48]. There are few marine-derived compounds in MI that have been investigated until now. Thus, in addition, a more detailed mechanistic study is needed.

4. Ischemic Heart Disease (IHD)

IHD is an inadequate blood supply of the coronary artery to the myocardium. Endothelial dysfunction is the main involvement in the mechanism of IHD [49]. It is the main cause of morbidity and mortality among all CVDs globally [50]. A 2016 report states it is responsible for 9 million deaths worldwide [51]. Marine-derived drugs are better than synthetic drugs to treat IHD due to their affective action and better results [44]. Histochrome, a sodium salt of echinochrome A, is a marine drug found as a common sea urchin pigment. It is a powerful and biosafe cell-priming agent that prevents cardiac progenitor cells (CPCs) from cellular apoptosis via the downregulation of BCL2-associated X (Bax) cleaved caspase-3, and phosphorylated histone, whereas upregulation of Bcl-xL and B-cell lymphoma 2 (Bcl-2) proteins, utilizing patient-derived human CPCs in treating heart disease [52]. In vitro study of echinochrome A (Ech A), a naturally occurring pigment from sea urchins, showed marine anti-thrombotics, especially sulfated polysaccharides, are relevant due to their distinct modes of action and absence of bleeding. Their distinct modes of action as an antithrombotic are due to the high negative charge that sulfation imparts, which enables them to interact with proteins and molecules involved in vital biological processes such as coagulation [53]. In addition, both polysaccharides Enteromorpha prolifera polysaccharides (EPPs), produced from green algae, and fucoidan, extracted from brown algae, have anti-oxidant, lipid-lowering, and antiangiogenic properties [54]. Alginate (ALG), mostly derived from brown seaweed, can lower TC, TG, and LDL-C serum levels and upregulate HDL-C concentrations, making it an effective treatment for coronary artery disease [55].

5. Cardiac Stroke

Cardiac stroke is the most severe complication of CVDs, causing sudden death. CVDs are mostly caused by cardiac arrest or stroke in individuals with elevated blood pressure, high cholesterol, obesity, increased blood glucose levels, and weight gain [56]. Natural compounds derived from marine sources have already been regarded as lead molecules for treating CVDs and cardiac arrest due to their varied chemical compositions and pharmacological characteristics [57]. A carotenoid molecule called fucoxanthin, obtained from brown algae, prevents lipids’ oxidation and buildup [58]. Fucoxanthin protects against cardiac stroke by regulating metabolic syndrome [59]. Another carotenoid, astaxanthin, showed a positive effect in cardiac stroke via the modulating number of biological processes, including the reduction in inflammation, augmentation of oxidative stress, enhancement of antioxidants, and the modification of lipid and glucose concentrations via suppressing TLR4/NF-κB/ROS signaling pathway [60]. A new type of unique structure called Xyloketal B contains a marine component derived from Xylaria species. Xyloketal B can benefit cardiac stroke due to its protective effect in the two-clip stroke-prone hypertensive model [61].

6. Cardiac Arrhythmia

Cardiac arrhythmias account for 10%–15% of fatalities, making them a substantial reason for morbidity and mortality worldwide [62]. Tetrodotoxin (TTX) is a marine compound obtained from the actinomycetes of marine sediments and has a beneficial effect on cardiac arrhythmia. It is also known as the puffer fish toxin that prevents sodium channels in excitable neurons [63]. It has also shown an antiarrhythmic effect in combinatorial therapy with lidocaine [64].
Many toxins, including tetrodotoxin, saxitoxin, brevetoxins, antillatoxin, conotoxins, and cnidarians, are found in marine species such as pufferfish, shellfish, sea anemones, and cone snails, are voltage-gated sodium channels (VGSCs) blockers, and show protective effects against cardiac arrhythmia [65]. Other marine drugs, omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, have shown antiarrhythmic effects against various arrhythmic disturbances, including atrial fibrillation and ventricular arrhythmia [66]. Eicosapentaenoic acid shows antiarrhythmic activity when added to the superfusate before adding the toxins, including ouabain, lysophosphatidylcholine, high Ca2+, acylcarnitine, β-adrenergic agonist, and the Ca2+ ionophore [30]. Botulinum toxin is obtained from the marine source Clostridium botulinum. Clostridium botulinum is a Gram-positive anaerobic spore-forming bacterium found in marine environments [67]. The botulinum toxin (BoNT/A1)–chitosan nanoparticles (BTN) formulation inhibits arrhythmia caused by sodium, calcium, and potassium channel activation [29].

7. Cardiac Dysfunction

Chronic cardiac dysfunction is caused by contractility overload on the heart myocardium. Different etiologies may favor existing compensatory mechanisms such as excentric (dilatation) and concentric hypertrophy. Chronic left ventricular dysfunction is the most prevalent complication of MI. Chronic cardiac dysfunction worsens left ventricular ejection fraction and stroke volume as dilatation progresses, eventually leading to heart failure [68]. Retinoid receptors play a crucial role in several diseases, including diabetes [69], cancer [70], and CVDs [71]. A research study reported that the retinoid receptor is essential for heart function. Moreover, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice showed significant diastolic dysfunction, increased intracellular ROS, NOX2 (NADPH oxidase 2), NOX4 and decreased antioxidant level (SOD1 and SOD2). This effect is reversed by overexpression of retinoid receptors [72]. In addition, Guleria RS et al. also demonstrated that retinoid receptors play a role in diabetic-induced cardiomyopathy [73]. In the same way, zeaxanthin heneicosylate (ZH) extracted from microalgae Dunaliella salina significantly reduced plasma biochemical alteration (AST, ALT, urea, and creatinine level), pro-inflammatory level (IL-6, NF-κB, and iNOS), antioxidant level (SOD), and histological changes in D-galactose-induced cardiac dysfunction rats through stimulating the retinoid receptors [32]. There are only a few studies on cardiac dysfunction; thus, detailed mechanistic studies are needed.

8. Heart Valve Disease or Valvular Heart Disease

Valvular heart disease (VHD) is a cluster of frequent cardiovascular disorders that account for 10–20% of all cardiac surgical operations in the United States. Heart valve problems include regurgitation (valve flaps do not close properly), stenosis (narrowed valve opening), and atresia (valve does not have a proper opening). Fucoxanthin is a marine carotenoid obtained from the seaweed microalgae Phaeodactylum tricornutum and possesses antioxidant and anti-inflammatory properties [74]. A report by Chiang et al. demonstrated the protective potential of heart valves in heart valve interstitial cells and dogs. Results showed that fucoxanthin treatment significantly reduced H2O2-induced ROS level, DNA damage, cell survival, and protein-related apoptosis and calcification expression via modulating the Akt/ERK pathway. In addition, long-term (0.5 to 2 years) supplementation to the dog also improved the left atrium to aortic (LA/AO) dimension ratio and E/e value (indicate mitral valve inflow, mitral valve leakage, and left ventricular diastolic dysfunction) [31]. This suggests that marine-derived compounds hold a diverse therapeutic potential. In addition, marine drugs which hold biological effects in CVDs tubulated in Table 2.

This entry is adapted from the peer-reviewed paper 10.3390/md21030193


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