Atherosclerosis is a chronic inflammatory disease characterized by the formation of lipid deposits, immune cell infiltration, and fibrosis in the arterial wall, eventually leading to atherosclerotic plaque formation (42, 43). One of the initial events in atherosclerosis is the accumulation of LDL in the subendothelial space of arteries (44, 45). In these regions, LDL becomes susceptible to oxidation by ROS, forming ox-LDL (46). ox-LDL not only exhibits pro-inflammatory properties but also activates various immune responses (46). ox-LDL binds to scavenger receptors on endothelial cell (EC), macrophages, and smooth muscle cells, triggering intracellular signaling pathways that initiate inflammatory responses (47). For instance, ox-LDL activates the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, promoting the expression of various pro-inflammatory cytokines and chemokines like IL-6 and TNF-α (47, 48). Ox-LDL has different effects on vascular smooth muscle cells (VSMCs) and ECs (49, 50). In ECs, ox-LDL activates the NF-κB pathway through Toll-like receptors (TLRs) and other receptors, increasing the expression of pro-inflammatory cytokines such as IL-6, Interleukin-8 (IL-8), and Monocyte Chemoattractant Protein-1 (MCP-1), which attract monocytes to the vessel wall and promote plaque formation (51). In VSMCs, ox-LDL also activates the NF-κB pathway but primarily promotes cell proliferation and migration, influencing plaque stability or instability (52). Additionally, the phenotypic switch of VSMCs from a contractile to a synthetic phenotype is associated with NF-κB activation (52).

The presence of ox-LDL and lipid accumulation in the arterial wall further induces the overproduction of pro-inflammatory cytokines (such as IL-6 and TNF-α) and chemokines, such as Chemokine (C-C motif) ligand 2 (CCL2) and Chemokine (C-X-C motif) ligand 10 (CXCL10) (53, 54). These molecules bind to their respective receptors on EC and immune cells, further amplifying the inflammatory response. IL-6 and TNF-α activate the Janus Kinase—Signal Transducer and Activator of Transcription (JAK-STAT) and NF-κB signaling pathways, promoting inflammatory responses and stimulating the proliferation and migration of vascular wall cells (55, 56). Chemokines (like CCL2) recruit monocytes to the arterial wall, enhancing the local immune response (57). CCL2 binds to the Chemokine (C-C motif) receptor 2 (CCR2) on monocytes, facilitating their adhesion to the endothelium and subsequent infiltration into the vascular wall (57). As atherosclerosis progresses, the accumulation of cholesterol and its metabolites triggers additional inflammatory responses by activating the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, a key intracellular inflammatory signaling complex (58). Activation of the NLRP3 inflammasome leads to Cysteine-aspartic protease 1 (caspase-1) activation, which promotes the conversion of Pro-Interleukin-1β (pro-IL-1β) and Pro-Interleukin-18 (pro-IL-18) into their mature forms, Interleukin-1β (IL-1β) and Interleukin-18 (IL-18) (59, 60). These cytokines further amplify local inflammation and induce apoptosis and necrosis of vascular wall cells (60). Activation of the inflammasome is also associated with plaque instability, potentially leading to plaque rupture and thrombosis, which can trigger acute cardiovascular events such as myocardial infarction and stroke (61).

In the early stages of atherosclerosis, EC become activated due to various risk factors such as ox-LDL, hyperglycemia, and hypertension (62). Activated EC express various adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and Endothelial Selectin (E-selectin) (63). The upregulation of ICAM-1 and VCAM-1 is a hallmark of endothelial cell activation (64). These molecules bind to integrins on monocytes, promoting firm adhesion of monocytes to the endothelium and their subsequent infiltration into the subendothelial space (65, 66). Endothelial cell activation also involves the release of pro-inflammatory cytokines like IL-1β and TNF-α, which further enhance endothelial adhesion and permeability, promoting monocyte migration (67). Monocytes that adhere to activated EC, guided by chemokines, cross the endothelial layer and infiltrate the intima (68). Once in the intima, monocytes differentiate into macrophages, which then phagocytose large amounts of ox-LDL through scavenger receptors (47). These macrophages, laden with excessive lipid, transform into foam cells (69). The formation of foam cells is a hallmark of atherosclerotic plaques and involves the release of various inflammatory mediators, further promoting the development of local inflammation (69, 70). The apoptosis and death of foam cells contribute to plaque instability by releasing large amounts of lipids and cellular debris, increasing the risk of plaque rupture and thrombosis (71).

In the progression of atherosclerosis, smooth muscle cells undergo proliferation and a shift towards a synthetic phenotype under the influence of inflammatory mediators (72). This process involves a phenotypic change that enables smooth muscle cells to produce extracellular matrix components such as collagen, forming fibrous caps and thickening the arterial intima (73). Smooth muscle cell proliferation and synthetic phenotype transformation play a critical role in stabilizing plaques (74). However, as the disease progresses, the apoptosis and necrosis of smooth muscle cells can lead to the rupture of fibrous caps, increasing plaque instability and the risk of cardiovascular events (75). In summary, the inflammatory mechanisms of atherosclerosis involve complex interactions among multiple cells and molecules. In Figure 1, the molecules and cells involved in the inflammatory microenvironment of atherosclerosis can be seen. The oxidation of LDL, the release of pro-inflammatory cytokines, the role of cholesterol metabolites, and the dynamic changes in EC, monocytes, and smooth muscle cells all contribute significantly to the progression of this disease.

Hypertension is a complex chronic disease with pathophysiological mechanisms involving multiple aspects, with inflammatory mechanisms receiving increasing attention in recent years (76, 77). Inflammation not only serves as a consequence of hypertension but also plays a crucial role in its progression and maintenance. The Renin-Angiotensin System (RAS) plays a pivotal role in the pathogenesis and progression of hypertension, with Angiotensin II (Ang II) being the key effector molecule (78). Ang II, by binding to the Angiotensin II type 1 receptor (AT1R), activates multiple signaling pathways, leading to vasoconstriction, sodium and water retention, and increased blood pressure (79). These inflammatory mediators further attract and activate immune cells, leading to vascular wall inflammation. ROS, including superoxide, hydrogen peroxide, and hydroxyl radicals, play significant roles in the inflammatory mechanisms of hypertension (80). Ang II increases ROS production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, which can directly damage vascular EC and activate inflammatory signaling pathways (81). In hypertensive patients, the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) often decreases, leading to weakened ROS clearance and further exacerbating oxidative stress and inflammation (82).

Endothelial dysfunction is a critical aspect of inflammatory mechanisms in hypertension (83). Upon exposure to Ang II, ROS, and other stimuli, EC release molecules like endothelin-1 (ET-1) and VCAM-1, which promote vasoconstriction and increase leukocyte adhesion and infiltration, leading to vascular wall inflammation (84, 85). Under normal conditions, EC produce nitric oxide (NO) through endothelial nitric oxide synthase (eNOS), which has vasodilatory and anti-inflammatory effects (86, 87). However, in hypertension, eNOS activity declines, reducing NO production, resulting in vasoconstriction and heightened inflammation (88). The immune system plays a crucial role in the inflammatory mechanisms of hypertension, with lymphocytes, particularly T cells, being significantly involved (89). In hypertensive patients and animal models, there is significant infiltration of T cells around blood vessels and in renal tissues (90). These T cells release cytokines such as interferon-γ (IFN-γ) and interleukin-17 (IL-17), further promoting local inflammatory responses (91). T Helper 1 (Th1) cells primarily secrete IFN-γ, which activates macrophages and promotes inflammation; T Helper 17 (Th17) cells mainly secrete IL-17, which is involved in neutrophil recruitment and activation (91, 92). These cytokines work together to cause chronic inflammation in blood vessels and kidneys, further maintaining and exacerbating hypertension.

The inflammatory mechanisms in hypertension are a complex process involving multiple interactions at both molecular and cellular levels. Figure 1 shows the molecules and cells involved in the inflammatory microenvironment of hypertension. At the molecular level, activation of the RAS, particularly the pro-inflammatory effects of Ang II, and exacerbation of oxidative stress, are crucial drivers of inflammation. At the cellular level, endothelial dysfunction and the involvement of lymphocytes, particularly T cells, further promote local and systemic inflammatory responses. A deeper understanding of these mechanisms not only elucidates the pathophysiological basis of hypertension but also provides a theoretical foundation for developing new anti-inflammatory therapeutic strategies.

Diabetes is classified into three primary types: type 1, type 2, and gestational diabetes (93–96). Diabetes is a long-term condition associated with various complications (97–105). Among these, diabetic cardiomyopathy (DCM) is a common and severe complication, characterized by myocardial dysfunction, cardiac remodeling, and heart failure (106). Inflammation plays a crucial role in the initiation and progression of DCM (107). In a hyperglycemic state, excess glucose can undergo non-enzymatic reactions with proteins, lipids, or nucleic acids to form advanced glycation end products (AGEs) (108). The formation of AGEs is a significant trigger of chronic inflammation in diabetic patients (109). In high glucose conditions, glucose reacts with proteins and lipids through the Maillard reaction to form Schiff bases, which then undergo Amadori rearrangement to produce stable AGEs (110). AGEs bind to their specific receptor, the receptor for advanced glycation end products (RAGE), and activate various pro-inflammatory signaling pathways (111). RAGE, a member of the immunoglobulin superfamily, is widely expressed in cardiomyocytes, EC, and macrophages (112). The binding of AGEs to RAGE can initiate multiple pro-inflammatory signaling cascades (113). Upon AGE-RAGE binding, the IκB kinase (IKK) complex is activated, leading to the phosphorylation and degradation of the inhibitory protein Inhibitor of κB alpha (IκBα) (114). This releases NF-κB, enabling its translocation to the nucleus and initiating the transcription of pro-inflammatory genes such as TNF-α and IL-6 (114). The AGE-RAGE complex can also activate the mitogen-activated protein kinase (MAPK) pathway (115). These kinases promote the expression of inflammatory factors and contribute to apoptosis (115).

Insulin resistance, a hallmark of T2D, is closely associated with inflammatory responses (116). Insulin resistance induces oxidative stress, leading to increased production of ROS, which in turn activates the expression of pro-inflammatory factors (117). In insulin-resistant states, the activity of NADPH oxidase and the mitochondrial electron transport chain increases, leading to elevated ROS production (118). ROS can activate multiple signaling pathways, including NF-κB and MAPK, promoting the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which further exacerbate myocardial inflammation and damage (119). Myocardial cells are severely damaged under the dual impact of high glucose toxicity and inflammatory factors (120). A high glucose environment directly causes metabolic disturbances in cardiomyocytes, including imbalances in glycolysis and fatty acid oxidation, leading to energy metabolism disorders and cell damage (121). Pro-inflammatory cytokines such as TNF-α and IL-6 activate apoptotic signaling pathways, including the Caspase family and B-cell Lymphoma 2 (Bcl-2) family, leading to myocardial cell apoptosis (122). High glucose and AGEs can activate EC through the NF-κB pathway (123). The cardiac microvascular system in diabetic patients is severely affected by inflammation, leading to coronary microcirculatory disorders, which further exacerbate myocardial ischemia and injury (124). As depicted in Figure 1, in diabetic cardiomyopathy, a high-glucose environment induces the formation of AGEs, which activate pro-inflammatory pathways through the RAGE. Additionally, insulin resistance increases pro-inflammatory factors related to oxidative stress. Myocardial cells are damaged, and microvascular inflammation leads to coronary microcirculatory dysfunction, exacerbating heart injury.

Obesity-related CMD are closely associated with chronic low-grade inflammation (125). Key mechanisms include inflammation in adipose tissue, insulin resistance, and cardiac inflammation (126). Recent research has highlighted the role of gut microbiota in the inflammatory microenvironment of CMD (127). Impaired gut barrier function, reduced production of short-chain fatty acids (SCFAs), and increased generation of microbial metabolites like trimethylamine N-oxide (TMAO) are all linked to the development and progression of CMD (128, 129). Future research needs to further explore individual variations in gut microbiota, interactions with the host immune system, and potential interventions based on gut microbiota.

From a systems biology perspective, integrating multi-omics data can provide a comprehensive theoretical framework and data support for elucidating the mechanisms underlying the formation of the inflammatory microenvironment in CMD. Firstly, genomics analysis can reveal genetic variations associated with CMD inflammation and identify potential risk genes (130). Secondly, proteomics data can elucidate the functions and interaction networks of key proteins in the inflammatory microenvironment, revealing the roles of proteins in signal transduction and functional regulation (131). Simultaneously, metabolomics research can capture the dynamic changes in metabolites during the inflammatory process, revealing the critical roles of metabolic pathways in inflammation regulation (132). This integrated analysis not only helps to uncover the complex regulatory network of the CMD inflammatory microenvironment but also provides a theoretical foundation and experimental basis for developing precision intervention strategies based on specific targets, thereby promoting the advancement of CMD-related research to a deeper level.