# Therapeutic Potential of Seaweed-Derived Bioactive Compounds for Cardiovascular Disease Treatment
## 2 Seaweed-Derived Phlorotannins with Therapeutic Potential against CVD  
Phlorotannins are polyphenol molecules generated as secondary metabolites by seaweed and consist of polymerization of phloroglucinol (1,3,5-tryhydroxybenzene) monomer units, which are biosynthesized via the acetate-malonate pathway, also known as the polyketide pathway [17]. In particular, some phlorotannins can be found exclusively in brown seaweeds, such as _Ecklonia_ species [18]. Phlorotannins can be classified into four subclasses according to the type of linkage between the phloroglucinol units. Fuhalols and phlorothols, as well as phloroglucinol units, are linked by aryl ether bonds. Fucols are composed of phloroglucinol units linked with aryl-aryl bonds. Fucophlorotechols are linked to ether and phenyl bonds. Eckols and carmalols are characterized by the presence of dibenzodioxin units and differ from carmalol in that they generally have a lower molecular weight and a phenoxyl moiety at C4 [19; 20]. Many researchers have revealed various beneficial biological activities of phlorotannins (mainly brown seaweed such as _Ecklonia_ and _Islige_ species), including anti-oxidant, anti-cancer, anti-bacterial, anti-allergic, anti-mutagenic, anti-diabletic, anti-inflammatory, anti-proliferative, anti-hypertensive, and anti-obesity effects [18; 21; 22; 23; 24]. Therefore, phlorotannins have been recognized for many years as promising bioactive compounds with health benefits for preventing and treating various human diseases. Hypertension is known as a major risk factor for cardiovascular disease (CVD). Normally, the anti-hypertensive ability is determined as the IC\({}_{50}\) value, which represents the angiotensin-converting enzyme (ACE) inhibitor concentration causing 50% inhibition of ACE activity. Captopril, a well-known ACE inhibitor, exhibits competitive inhibition [25]. Additionally, several previous studies have confirmed that phlorotannins such as eckol [26; 27], dieckol [26; 27], 6,6\({}^{\prime}\)-bieckol [28], phloroglucinol [26; 27], phlorofucoflueroeckol A [27], triphloroth-A [26; 27], ecstolololol [26; 27], tucosterol [27], and octaphloroth A [29], isolated from _Ecklonia cava_, _Ecklonia stolonifera_, and _Islige foliaca_, showed non-competitive  
Figure 1: The preventive potential of various seaweed-derived natural components associated with cardiovascular disease (CVD) pathogenesis, such as diabetes mellitus, obesity, hypertension, and hyperlipidemia. ACE inhibition (Table 1). These phlorotannins demonstrated ACE inhibitory activity similar to or even higher than that of captopril. In addition to ACE inhibition, vasodilators also contribute greatly to the anti-hypertensive properties. NO is a well-known vessel-relaxing factor produced from L-arginine by endothelial nitric oxide synthase (eNOS) in the presence of oxygen and the cofactors Ca\({}^{2+}\) and calmodulin (CaM) [30]. A previous study has indicated that genetically deficient eNOS mice are hypertensive with lower circulating NO levels, thus indicating the critical role of eNOS and NO in CVD [5; 9]. It has also been reported that multiple mechanisms control NO production via eNOS activation [31]. The phosphatidylinositol 3-kinase (PI3K) pathway members, including their downstream molecule, protein kinase B (Akt), are essential regulators. Activated Akt would directly phosphorylate ser1177 on eNOS, enhancing the [Ca\({}^{2+}\)]/CaM complex [32]. Second, the concentration of intracellular Ca\({}^{2+}\) ([Ca\({}^{2+}\)]) in ECs and VSMCs is closely related to the vascular tone and influences blood pressure [33]. Third, the L-type calcium channel is one of the critical ion channels that regulates vasoconstriction and vasodilation. Nitrodilators promote vasodilation by increasing soluble guanylyl cyclase (cGMP) and decreasing the [Ca\({}^{2+}\)] levels in VSMCs. These actions would reduce the phosphorylation of the Ca\({}^{2+}\)-sensitive myosin light chains, resulting in vasodilation [34]. One study demonstrated that [PERSON] et al.