## 4 Effect of PS on Cardiovascular Diseases Linked to MetS
This effect was achieved by inhibiting the nuclear factor-kappa B (NF-kB) pathway, evidenced by a reduction in TNF-\(\alpha\)-stimulated NF-kB p65 subunit expression [133]. TNF-\(\alpha\)-stimulated HUVECs supplemented with the aqueous leaf extract of PS (150, 250, and 300 mg/mL for 24 h) showed decreased ADMA levels, increased NO levels, and an increased expression of dimethylarginine dimethylaminohydrolase 1 (DDAH 1) mRNA and protein [135]. Similarly, H\({}_{2}\)O\({}_{2}\)-stimulated HUVECs supplemented with the aqueous leaf extract of PS (150 mg/mL for 24 h) showed an increased mRNA and protein expression and enzymes activity of eNOS and an increased production of NO [136]. Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme that degrades ADMA [137], and a decrease in its activity leads to an increase in ADMA, which reduces eNOS activity and NO production [138]. A reduced nitric oxide synthesis due to eNOS downregulation plays a significant role in vasoactive factor imbalance, endothelial haemostasis impairment, and the early development of atherosclerosis [139]. These studies suggest that PS could reduce the risk of endothelial dysfunction and atherosclerosis due to its anti-inflammatory properties through the inhibition of the NF-kB pathway and stimulation of the DDAH/NOS pathway. An increase in inflammatory markers is linked to hypercholesterolemiaicmic atherosclerosis. In animal studies, high cholesterol diet (HCD)-induced atherosclerotic rabbits treated with the aqueous leaf extract of PS (500 mg/kg/day for 10 weeks) showed decreased ICAM, VCAM, and C-reactive protein (CRP) [140]. CRP is important in the pathogenesis of the vascular inflammatory process. It promotes endothelial cells to express ICAM-1 and VCAM-1 [141], suggesting that PS may help to reduce the inflammation linked to the development of atherosclerosis due to hypercholesterolemiaemiaemia. The aqueous leaf extract (500 mg/kg/day for 10 weeks) decreased the fat deposit and atherosclerotic lesion in the aortic intima layer of atherogenic rabbits [142]. The PS aqueous leaf extract (250 and 500 mg/kg/day for 10 weeks) [142] and the methanolic leaf extract (62.5, 125, and 250 mg/kg/day for 10 weeks) [22] reduced the thickening of the intima ratio, neointimal area, fatty streak, and foam cells covering the intima layer in the abdominal aorta of atherogenic rabbits. This implies that PS supplementation could reduce the blood vessel narrowing associated with atherosclerosis by preventing fat deposition and reducing atherosclerotic lesions in hypercholesterolemiaic rabbits. Rabbit is a better model of atherosclerosis because rats are resistant to atherogenesis [143], even at a 10% \(w\)/\(w\) cholesterol diet [143]. This is because lipid metabolism in rats is primarily based on high-density lipoprotein (HDL), rather than LDL, as is the case in humans [144]. As a result, additional agents such as vitamin D3 are frequently required to produce atherosclerotic calcification or aortic calcification in rats [145]. On the other hand, rabbits and hamsters are sensitive to dietary cholesterol-induced atherosclerosis [146]. In particular, hamsters carry a significant portion of their plasma cholesterol in LDL particles, making them similar to humans [147] and sensitive to high-fat diets [148]. Several studies have implicated DM in the development of cardiac dysfunction and atherosclerosis as metabolic deterioration in DM leads to structural and biochemical changes in the heart [84]. STZ-induced diabetic rats treated with the aqueous leaf extract of PS (125 mg/kg/day for 28 days) showed reduced disturbance and irregular arrays of myofibrils within the sarcomere of cardiac tissues. The size, disruption, and patchy areas of cytoplasmic space in the mitochondria of cardiac tissue were also reduced [84]. Similarly, [PERSON] et al. [149] reported a decreased deformation in the sizes and shapes of the cardiomyocyte's nuclei of cardiac tissue.