Bioactive peptides are a class of functional protein fragments with molecular weights below 10 kDa, typically produced by in vitro hydrolysis, in vivo digestion, or microbial fermentation of proteins. The biological activities of bioactive peptides are closely related to their unique amino acid composition and structures [1-2].

Compared with traditional chemical drugs, bioactive peptides have lower toxic and side effects on the human body, are easily digested and absorbed, and exhibit high bioavailability. In addition, bioactive peptides possess various physiological functions such as antihypertensive, antioxidant, hypoglycemic, hypolipidemic, and immunomodulatory activities, which have attracted extensive attention from the scientific community [3].

Among them, bioactive peptides with antihypertensive, hypoglycemic, and hypolipidemic effects are collectively referred to as cardiovascular active peptides. Plant-derived active peptides are active polypeptides extracted and prepared from plant raw materials. Compared with synthetic peptides, plant-derived active peptides have higher safety; in contrast to animal-derived active peptides, abundant plant resources significantly reduce their production costs, conferring greater economic advantages. At present, the incidence of cardiovascular diseases continues to rise. Owing to their high safety, specificity, and bioavailability, plant-derived cardiovascular active peptides are expected to become effective alternatives for the treatment and prevention of cardiovascular diseases [4].

This paper focuses on reviewing the mechanisms of action and applications of cardiovascular active peptides, aiming to provide a theoretical basis for the further development and application of plant-derived cardiovascular active peptides.

Mechanisms of Action and Applications of Cardiovascular Active Peptides

Cardiovascular diseases refer to a group of disorders involving the heart and blood vessels, including coronary heart disease, hypertension, and heart failure. The accelerated pace of life and unhealthy lifestyles have led to a rapid increase in their incidence, posing a serious threat to public health and increasing the medical burden [37]. Bioactive peptides are crucial for maintaining the homeostasis of the cardiovascular system due to their advantages of small molecular weight, simple structure, and high bioavailability. Studies have shown that the functions of active peptides mainly focus on antihypertensive, hypolipidemic, hypoglycemic, antioxidant, and antibacterial activities [11].

Mechanisms of Action and Applications of Antihypertensive Peptides

The prevalence of hypertension is gradually increasing due to accumulated life stress, disordered diet, and irregular work-rest schedules. Although antihypertensive drugs such as ACE inhibitors, β-blockers, and calcium channel blockers play a key role in blood pressure regulation, long-term administration may induce side effects including upper respiratory tract stenosis, edema, and even cancer [38]. With the advancement of research on bioactive peptides, plant-derived antihypertensive peptides, with their high safety and bioavailability, can serve as potential substitutes or supplements for traditional antihypertensive drugs.

Blood pressure regulation in the human body relies on the complex interplay of the neurohumoral system, mainly involving the renin-angiotensin-aldosterone system (RAAS), natriuretic peptide system, endothelin system, kallikrein-kinin system, as well as the sympathetic nervous and immune systems (Figure 1) [39]. Renin converts angiotensinogen to angiotensin I, which is further catalyzed by ACE to form angiotensin II, thereby enhancing myocardial contractility and inactivating bradykinin, leading to elevated blood pressure [40]. Therefore, ACE inhibition is considered a key strategy for blood pressure regulation, and ACE serves as an important target for antihypertensive drugs [32]. Abundant plant resources represent a vital source of cardiovascular active peptides such as ACE-inhibitory peptides. Moreover, plant-derived antihypertensive peptides not only effectively lower blood pressure but also reduce drug side effects, providing new options for hypertension treatment [23, 41].

Studies have demonstrated that the ACE-inhibitory efficacy of antihypertensive peptides is associated with the binding strength between their amino acid residues and the active site of ACE. Polypeptides with low molecular weights, especially those < 3 kDa, are more prone to binding to the ACE active site and exhibit higher antihypertensive potential [40]. Aondonna et al. [38] isolated sesame polypeptides < 1 kDa with the strongest ACE-inhibitory activity. Animal experiments showed that a novel ACE-inhibitory peptide SSYYPFK with a molecular weight of 890.4 Da, isolated and identified from naked oat globulin hydrolysates, significantly reduced blood pressure in hypertensive rats [41]. The antihypertensive activity of polypeptides is also related to the type of proteases. Differences in protease cleavage sites lead to variations in polypeptide sequences, thereby affecting their activity [41]. For example, alkaline protease produces peptide chains containing hydrophobic amino acids; trypsin tends to cleave peptide bonds of aromatic amino acids or uncharged branched-chain amino acid residues; pepsin preferentially cleaves hydrophobic and aromatic residues [42]. In addition, the activity of antihypertensive peptides is affected by polypeptide structure. Zhao et al. [43] constructed a dataset using ACE-inhibitory tetrapeptides identified from traditional fermented soybean products, established a quantitative structure-activity relationship model to screen polypeptides with high ACE-inhibitory activity, and found that the characteristics of amino acids at both termini more significantly affect activity, with lower hydrophobicity, smaller steric hindrance, and higher electrostatic properties corresponding to stronger inhibitory activity. The activity of ACE-inhibitory peptides is also closely related to the arrangement of amino acid residues and spatial conformation. For instance, inhibitory peptides with aliphatic amino acids (glycine, valine, alanine, leucine, etc.) at the N-terminus can form multiple interactions with ACE including hydrogen bonds, electrostatic forces, and hydrophobic forces, thereby enhancing their activity [44].

Although long-term administration of antihypertensive drugs is effective, their adverse reactions may compromise health. As novel therapeutic and preventive agents, plant-derived antihypertensive peptides will accelerate the replacement of traditional drugs [45]. Furthermore, antihypertensive peptides can be used as functional food additives to help regulate bodily functions and maintain stable blood pressure. For example, rice protein hydrolysates can be applied in the prevention or treatment of hypertension [5].

Mechanisms of Action and Applications of Hypoglycemic Peptides

Diabetes is an intractable chronic metabolic disorder characterized by elevated blood glucose caused by insulin resistance or insufficient secretion, which disrupts metabolic homeostasis and carries the risk of complications [46]. In recent years, the incidence of diabetes has risen sharply, making it a major public health concern [47]. Common hypoglycemic pathways include inhibiting hepatic glycogenolysis (reducing glucagon secretion), gluconeogenesis (increasing insulin secretion and reducing glucagon secretion), and polysaccharide decomposition (inhibiting α-glucosidase and α-amylase activities) to suppress glucose production and lower blood glucose; promoting glycogen synthesis, glucose conversion to fats and proteins, and other processes to increase glucose consumption in serum and reduce blood glucose levels [48]. Clinically, hypoglycemic drugs include injectable insulin preparations and oral medications, with the latter improving patient compliance. Hypoglycemic drugs primarily exert effects by inhibiting the activities of α-amylase, α-glucosidase, and dipeptidyl peptidase-IV (DPP-IV), as well as activating GLP-1 receptors (Figure 2) [49-50].

The treatment of diabetes and its complications represents a major medical challenge, and the discovery of hypoglycemic peptides has provided new strategies. Studies have shown that soybean polypeptides with molecular weights < 5 kDa significantly inhibit α-glucosidase, while those > 10 kDa exhibit α-amylase inhibitory activity; germinated soybean protein hydrolysates also show strong DPP-IV inhibitory activity [51]. Karimi et al. [52] found that corn germ protein hydrolysates < 2 kDa exhibited the optimal α-glucosidase inhibitory effect, whereas alkaline protease hydrolysates with molecular weights of 2–10 kDa significantly inhibited α-amylase and DPP-IV, indicating that the hypoglycemic effect of hydrolyzed polypeptides is related to the type of proteolytic enzyme. Wang et al. [53] evaluated the in vitro hypoglycemic effect of walnut hydrolyzed peptides and found that hydrolysates with molecular weights of 3–10 kDa significantly inhibited α-glucosidase activity. Further studies revealed that this peptide effectively reduced fasting blood glucose and increased insulin secretion in mice. Research has also indicated that the activity of hypoglycemic peptides is related to their structure. Small-molecular-weight polypeptides are more easily absorbed by the human body and exert better hypoglycemic effects; thus, hypoglycemic peptides usually consist of 2–15 amino acid residues. In addition, polypeptides with hydrophobic amino acids such as proline at the N-terminus can effectively inhibit DPP-IV activity, although some studies suggest that hydrophobic amino acids are not a prerequisite for the hypoglycemic activity of polypeptides [54].

Plant-derived bioactive peptides play an important role in maintaining blood glucose homeostasis due to their significant hypoglycemic effects. However, protein hydrolysis often produces a mixture of various peptides, requiring further separation and purification [11]. Therefore, obtaining highly pure and novel hypoglycemic active polypeptides is a limiting step for their application as blood glucose-regulating drugs or functional food additives.

Mechanisms of Action and Applications of Hypolipidemic Peptides

With improved living standards and an accelerated pace of life, sedentary behavior, lack of exercise, and high-cholesterol food intake are key factors leading to dyslipidemia and metabolic diseases such as obesity and hypertension [11, 55-56]. The core of hypolipidemic intervention is to regulate cholesterol and triglyceride (TG) levels. Currently, a wide variety of lipid-lowering drugs are available on the market, but single drugs such as statins require high dosages, and long-term use may cause adverse reactions including drug resistance, gastrointestinal reactions, and liver damage. In contrast, lipid-lowering active peptides possess advantages such as green safety, small molecular weight, strong permeability, high specificity, and targeted activity [55]. Proprotein convertase subtilisin/kexin type 9 inhibitors are novel lipid-lowering drugs that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels, but currently only monoclonal antibody formulations are used clinically [57].

Lipid-lowering drugs are classified into statins and non-statins. Statins exert lipid-lowering effects by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, to reduce LDL-C production [58]. Non-statin drugs regulate lipid balance by acting on corresponding targets to reduce the production of LDL-C, TG, and Lp(a) and increase high-density lipoprotein cholesterol (HDL-C) levels [59]. Compared with traditional drugs, plant-derived active peptides have high specificity and low side effects, showing broad prospects in the prevention and treatment of dyslipidemia-related diseases. Studies have shown that perilla seed meal polypeptides significantly reduce total cholesterol (TC), TG, and LDL-C levels in hyperlipidemic mice [55]. Walnut meal peptides improve lipid metabolism and protect the liver in high-fat diet-fed rats by reducing TC and TG levels in serum and liver [60]. Pancreatic lipase (PL) and cholesterol esterase (CE) are key enzymes for hypolipidemic effects. Hypolipidemic peptides reduce intestinal fat absorption and serum cholesterol levels by inhibiting PL or CE activities. The polypeptide FPFVPAPT isolated from amaranth protein promotes cholesterol metabolism by inhibiting CE activity [56]. Many food-derived active peptides exert lipid-lowering effects through hydrogen bonding, hydrophobic interactions, and other bindings with PL or CE [61]. For example, polypeptides in seabuckthorn seed meal protein hydrolysates inhibit PL or CE activities through interactions with these enzymes [62]. In addition, hypolipidemic peptides are expected to provide safe and effective preventive measures for patients with hyperlipidemia in the development of functional foods.

Other Mechanisms of Action and Applications

Plant-derived active peptides also exhibit antioxidant, antibacterial, anticancer, and immunomodulatory activities. Studies have found that antioxidant peptides < 3 kDa isolated from mung bean and perilla seed protein hydrolysates can serve as sources of natural antioxidants [24-25]. Trypsin hydrolysates of highland barley protein show inhibitory effects on Bacillus subtilis, Escherichia coli, and other bacteria, with broad-spectrum activity [63]. Highly active anticancer peptides have been screened from quinoa using a colon cancer cell model [36]. In addition, active peptides derived from soybean and pea exert immunomodulatory effects by binding to immune cell receptors and inducing the production of cytokines or antibodies [1, 3]. Thus, plant-derived active peptides often possess multiple biological activities and act through diverse mechanisms, providing potential strategies for the prevention and treatment of chronic diseases [1] and serving as natural additives for functional foods [21].

Summary and Outlook

Current research on cardiovascular active peptides is still in the preliminary stage, facing challenges such as inefficient enzymatic hydrolysis, complex separation, and difficulties in high-throughput screening. Most existing studies on active peptides focus on the in vitro level, and the in vivo efficacy in animal models and clinical performance of plant polypeptides with high in vitro activity require further verification. Therefore, under the guidance of the national Healthy China strategy, the industrialization of plant-derived active peptides faces multiple challenges:

① Expanding plant sources: Abundant plant resources exist in nature, but current research on active peptides mainly focuses on leguminous plants. More sources of cardiovascular active peptides can be explored.

② Optimizing preparation processes: Although existing preparation technologies are mature, there is still room for improvement. For example, genetic engineering can be used to improve plant varieties and increase active peptide content, or more efficient extraction and purification methods can be developed.

③ In-depth exploration of mechanisms of action: The mechanisms by which active peptides regulate cardiovascular diseases are not fully understood. Further studies on the material basis and regulatory mechanisms of active peptides in cardiovascular diseases are needed to provide scientific evidence for clinical application.

④ Expanding application fields: In addition to food and pharmaceuticals, plant-derived cardiovascular active peptides can also play important roles in cosmetics and health products, with great potential for market expansion.

⑤ Improving industry standards for polypeptides: At present, there are only 6 national standards, 8 industry standards, and 4 enterprise standards for polypeptides in China, which cannot meet the needs of the polypeptide health industry. The development of plant-derived polypeptides is accelerating, but strict standards for production, quality evaluation, and industrial application are lacking.

In summary, the discovery of novel plant-derived cardiovascular active peptides and exploration of their mechanisms of action are expected to lead to the development of more precise and efficient therapeutic strategies, providing more natural and safe treatment options for patients with cardiovascular diseases.

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