Adiponectin is a polypeptide specifically secreted by adipocytes, which was first identified in adipocytes and has high expression during adipocyte differentiation, and its monomer protein molecular weight is 30 kDa (19). The structure of the adiponectin monomer consists of four parts: the signal sequence at the amino end, the collagen domain, the highly variable nonhomologous sequence and the carboxyl end spherical domain (19). To date, three types of adiponectin receptors have been discovered based on their capability to bind to adiponectin. Adiponectin receptor 1 and 2 (AdipoR1 and AdipoR2), as well as T-cadherin (20, 21). AdipoR1 and AdipoR2 share a high level of structural similarity, with both proteins featuring seven transmembrane domains (20). T-cadherin is partially attached to the cell membrane via glycosylphosphatidylinositol, not transmembrane domains (21). Both the secretion and expression of adiponectin and the signal transduction of the adiponectin receptor play an important role in vascular homeostasis.

Adiponectin exhibits various beneficial effects, including promoting insulin sensitivity, preventing atherosclerosis, and reducing inflammation. It has a good inhibitory effect on various metabolic disorders, including type 2 diabetes, atherosclerosis, obesity, etc., and has a particularly prominent protective effect on the cardiovascular system (22–29). Epidemiological data and animal and cellular studies have yielded promising results on the cardioprotective effects of Adiponectin. There are extensive clinical epidemiological data suggesting a strong negative correlation between plasma levels of adiponectin and the occurrence rates of hypertension, left ventricular hypertrophy, and myocardial infarction (26, 30, 31). The findings indicate that the reduction in adiponectin levels could be a significant contributor to cardiovascular disease. Adiponectin affects the secretion of inflammatory factors via AMPK inhibition of the activated NF-kB signaling pathway, attenuating cardiac inflammation and high-fat diet-induced atherosclerosis. In pathological cardiomyocyte hypertrophy, Adiponectin inhibits cardiomyocyte hypertrophy by reducing markers that promote hypertrophy. In cardiac interstitial fibrosis, Adiponectin regulates cardiac interstitial fibrosis by affecting TGF-b and p-smad2/3 signaling pathways. A lot of research have shown that adiponectin contributes to glucose homeostasis and insulin sensitivity; however, adiponectin does not only protect blood vessels by improving insulin sensitivity. Some studies have provided evidence that low concentrations of adiponectin lead to a doubling of the risk of coronary heart disease compared to risk factors such as diabetes, hypertension and smoking (29). The results imply that adiponectin levels and cardiovascular disease risk are not influenced by blood glucose and lipid status, suggesting that adiponectin directly protects blood vessels rather than through insulin sensitivity and diabetes. High Adiponectin levels in the body tend to represent a healthier metabolic phenotype, however, Adiponectin also does not explain the beneficial phenotype in all healthy obese individuals. It has been shown that there is a paradox between Adiponectin and mortality in patients with cardiovascular disease, and that Adiponectin is positively associated with mortality in a variety of clinical conditions, including diabetes mellitus, which is related to confounding between lipocalin resistance and natriuretic peptides, and may be due to a combination of genetic, environmental, and dietary differences in different racial and regional populations.

PVAT affects the vascular response by increasing or inhibiting NO production (32–35). NO is synthesized by three NOS enzymes: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS) (36). The various roles of NO in atherosclerosis are connected to the sources of NO. NO from eNOS and nNOS has antiatherosclerotic effects, while NO from iNOS can promote the occurrence of atherosclerosis. In nNOS^-/-; ApoE^-/- mice, the aortic root and descending aorta showed greater atherosclerotic lesions and increased mortality (37). NO produced by nNOS in the cells of the central and peripheral nervous systems is involved in the regulation of blood pressure in the central nervous system as a neurotransmitter (38). Under normal physiological circumstances, there is no manifestation of iNOS within the vascular system. However, in instances of inflammation, sepsis, oxidative stress, and other pathological states, blood vessels exhibit iNOS. eNOS in PVAT directly produces and releases NO, affecting blood vessels (39). In addition, NO produced in PVAT positively regulates the release of adiponectin from PVAT (40). Therefore, improving NO secretion in PVAT is a promising target for cardiovascular disease therapy.

FGF-21, belonging to the fibroblast growth factor family, fulfills a vital function by combating inflammation in both obese adipose tissue and heart tissue. FGF-21 exhibits important anti-inflammatory effects in obese adipose tissue, cardiac tissue and macrophages (41–45). FGF-21 gene expression is reduced in adipose tissue from patients with multivessel coronary artery disease associated with T2DM and enhanced in adipose tissue from patients undergoing cardiac surgery, suggesting a protective effect of FGF-21 against inflammation associated with cardiac surgery (46, 47). Hence, the anti-inflammatory impact of PVAT is advantageous in safeguarding against and treating cardiovascular ailments. On the other hand, the main role of FGF21 as an adipokine is to influence cellular lipid metabolism by modulating key transactivated receptors (such like ABCA1/ABCG1) and reducing macrophage-to-foam cell transformation (48, 49). Recent studies have shown that FGF21 can also act as a predictor of atherosclerosis by inhibiting mitochondrial fragmentation to reduce ROS production, and ultimately reducing NLRP3-mediated cellular death in endothelial cells to resist atherosclerosis (50, 51). The multifaceted functions of FGF21 in insulin sensitisation, lipid metabolism and inflammatory modulation collectively assist in its resistance to the progression of cardiovascular disease.

One newly discovered adipocytokine called Omentin is found to be expressed in the omentum, epicardium, and perivascular adipose tissue (52, 53). Patients with heart failure have lower circulating levels of omentin, which attenuate myocardial ischemic injury by promoting mitochondrial biogenesis (54). Omentin exerts anti-inflammatory effects in smooth muscle cells by inhibiting TNF-α-induced VCAM-1 expression.Its mechanism may be associated with the inhibition of p38 and JNK activation (55). Omentin improves endothelial dysfunction in individuals with type 2 diabetes, and it also partially restores the loss of the anticontractile effect in PVAT. Additionally, Omentin treatment effectively enhances the pro-inflammatory and pro-oxidative phenotypes of PVAT (55). Omentin-1 was found to inhibit the expression of TGF-β1 in cardiomyocytes obtained from atrial fibrillation patients, reduce the activation of cardiac fibroblasts induced by TGF-β1, and reverse the endothelial-mesenchymal transition in HUVECs induced by TGF-β1 (56). Reduced levels of reticulin-1 in the circulation of patients with coronary artery disease (57, 58). Currently, there are fewer reports on the relevant role of Omentin in cardiovascular disease, mainly focusing on its ability to reduce vascular inflammation by affecting inflammatory factors such as TNFa and affecting vascular pressure through NOS-dependent pathways (59). Different research groups seem to have different views on the expression level of Omentin as a predictor in coronary heart disease (57, 60), which shows that there is still much unknown about its function as an adipokine in cardiovascular disease

Leptin is a non-glycosylated peptide hormone that is synthesized in adipocytes and has a molecular weight of 16 kDa. Leptin, a traditional proinflammatory adipokine, enhances the secretion of TNF-α, IL-6, and IL-12 by monocytes and increases the production of CC chemokine ligands (61, 62). It also promotes cell proliferation, reactive oxygen species (ROS) production, and the migratory response of monocytes (62). Furthermore, leptin is known to cause endothelial dysfunction by stimulating the production of C-reactive protein (CRP), cell adhesion molecules, and platelet tissue factor in endothelial cells (63). Increased levels of leptin have also been linked to obesity-related conditions such as myocardial infarction and stroke (64, 65). Leptin targets platelets, promotes platelet aggregation, stimulates platelet-dependent thrombosis and upregulates vascular adhesion molecules and prothrombotic tissue factor (66). The results indicate that leptin has the capacity to regulate cardiovascular disease. In a mouse model of atherosclerosis, Leptin intervenes in disease progression by affecting T-cell helper type 1 (Th1) response and promoting regulatory T-cell (Treg) function interferes with disease progression (67). In summary, Leptin’s main role is to influence vascular inflammation and regulate blood pressure in the body.

Resistin, an Adipokine with Potent Proinflammatory Properties. PVAT-derived resistin plays a key role in diabetic vasculature via a pathway that involves the activation of AP-1 (68). In addition, resistin enhances the expression of chemokines MCP1, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) and promotes the release of inflammatory factors, such as interleukin and TNF-α, through the activation of the NF-κB signaling pathway, ultimately causing endothelial dysfunction (69–71). Current research on Resistin in cardiovascular disease is primarily related to hypertension. Increased levels of Resistin are present in both T2D or hypoxic conditions or obesity-induced hypertension, suggesting a positive correlation between Resistin and blood pressure (72, 73).

ANG II functions primarily in cardiovascular disease to regulate blood pressure and vascular inflammation. ANG II, secreted by white and brown fat, regulates vascular tone and controls blood pressure. Mas receptor inhibition reduced the contractile and vasodilatory effects of exogenous ANG II on PVAT-denuded aorta. Ang II promotes inflammatory responses in PVAT and significantly downregulates oxidative phosphorylation in various regions of aortic PVAT, and the promotion of an adipocyte browning phenotype in aortic PVAT counteracts Ang II-induced inflammatory and oxidative effects (74). Ang II increases monocyte chemotactic protein-1 expression in the vascular wall and PVAT and Ang II-induced microvascular injury through modulation of the innate and adaptive immune responses (75). Thus, intervention in ANG II levels favors the regulation of blood pressure and vascular inflammation.

TNF-α exerts both a proinflammatory effect and promotes the production of other adipokines, such as IL-6, leptin and resistin. Obesity promotes the secretion of large amounts of TNF-a by adipocytes and macrophages in the PVAT, and TNF-a promotes aortic intimal-medial thickening (76). TNF-α induces migration and proliferation of smooth muscle cells from the medial side of the vessel wall to the intima through upregulation of intercellular cell adhesion molecule-1 (ICAM-1), scavenger receptor class A and MCP-1 expression, ultimately leading to endothelial dysfunction (77, 78). TNF-α increases cytosis of lipoproteins between endothelial cells and macrophages, ultimately leading to retention of LDL in the vessel wall (79). IL-1β promotes immune cell recruitment and increases vascular permeability, Clinical use of canakinumab offers promise for targeting IL-1b for atherosclerosis treatment (80–82). IL-6 is another significant cytokine that plays a role in regulating the inflammatory response to PVAT. IL-6 acts directly on endothelial cells to increase superoxide production, leading to endothelial cell dysfunction (83). IL-6 affects vascular smooth muscle cell migration and induces vascular mitochondrial dysfunction in atherosclerosis (84). IL-18 modulates inflammation and plaque stability to promote atherosclerosis, but it is unclear whether IL-18 independently predicts atherosclerosis (85, 86).

PVAT-derived chemokines promote the recruitment of monocytes and T cells and further promote the production of chemokines and inflammatory factors (87). The function of cytokines produced by dysfunctional PVAT is multifaceted. The release of cytokines such as TNF-α, IL-6, and Il-1β, on the one hand, results in inflammation of adipose tissue and dysfunction of endothelial cells. However, IL-10 released by PVAT can enhance endothelial function by suppressing oxidative stress and augmenting the production of nitric oxide. Inflammatory and anti-inflammatory factors co-exist in vascular inflammation to maintain vascular homeostasis

miRNAs, which are short, non-coding RNAs, can attach themselves to mRNAs, preventing their translation and subsequently impacting protein synthesis and various cellular processes. It has been shown that miRNAs in PVAT-secreted vesicles are associated with cardiovascular disease, for example, PVAT secretes extracellular vesicles containing miR-221-3p, which enhance the proliferation and migration of vascular smooth muscle cells, leading to vascular remodeling and dysfunction (88). Camila. et al. results suggest that miRNA-22 influences aortic reactivity in physiological circumstances and its deletion attenuates the loss of the NOS-mediated anticontractile effect of PVAT in obesity (89). According to reports, it has been stated that Perivascular adipose-derived exosomes decrease the formation of macrophage foam cells by upregulatingcholesterol efflux transporters ABCA1 and ABCG1 through miR-382-5p-and BMP4-PPARγ mediation (90). Although the current study confirmed that various miRNAs promote monocyte migration and pro-inflammatory. Although current studies haveconfirmedthat various miRNAs can promote monocyte migration and pro-inflammatory polarization and are involved in atherosclerosis, their specific roles in health and cardiovascular disease need to be further investigated (91).