Cardiovascular disease (CVD) now accounts for one-third of all fatalities globally, and it has recently emerged as one of the most significant variables affecting people's health (1). Coronary artery disease (CAD) is the most common type of CVDs and is caused by atherosclerotic blockage of the coronary arteries (2). Its clinical manifestations are usually myocardial infarction (MI) and ischemic cardiomyopathy (3). CAD is becoming more common every year in developed and developing countries, which is seriously endangering people's lives (3, 4). Inflammation, oxidative stress, autophagy, and apoptosis are the fundamental pathological reactions to CAD. The primary pathological processes are cell damage and excessive cellular autophagy (5). Additionally, CAD has the further pathophysiological features of vascular dysfunction and myocardial dysfunction. Previous research has demonstrated that endothelial damage causes reduced bioavailability of nitric oxide (NO), which throws off the delicate balance between vasoconstriction and diastole. The outcomes are increased endothelial permeability and endothelial secretion disorders, further resulting in vascular dysfunction (6). Cardiovascular dysfunction is an early event of CVDs such as atherosclerosis and heart failure and can be utilized as an early predictor for the assessment of heart failure (7–9). Therefore, cardiac vascular dysfunction has become a major potential target for the treatment of heart disease.

The cardiac microvascular endothelial cell (CMEC) is the first line of defense for tissues and organs and can be used to detect alterations in hemodynamic and blood propagation signals. Together with smooth muscle cells, it regulates blood flow and plays a critical role in regulating angiogenesis and inflammatory reactions (10). The primary cause of coronary microvascular dysfunction (CMD) is endothelial dysfunction occurring in the CMECs (11), and it leads to severe tissue damage. Damaged vascular endothelial cells can have an impact on other cells and aggravate the illness (12). Moreover, the damage to CMECs precedes cardiac myocytes in the development of CVDs (13). In the event of hypoxic or inflammatory injury, among others, CMEC not only regulates nutrient exchange and oxygen-carbon cycling in cardiomyocytes but also protects cardiomyocytes from damage (14). In the heart, multiple capillary-based CMECs tightly encircle the cardiomyocytes to create a perfusion unit. The space between the two cells is extremely narrow and contiguous. For example, NO has an important regulatory role in the cardiovascular system. Decreased NO activity can lead to increased coronary artery constriction and inflammation. Two NO-converting enzymes, constitutive NO synthase (cNOS; type III) and inducible NO synthase (iNOS, type II), are highly expressed in endothelial cells (15). The released NO affects cardiac diastolic function by raising cyclic guanosine monophosphate (cGMP) levels in cardiomyocytes. However, excessive NO can induce myocardial disorders under pathological conditions (16). Several studies have demonstrated that the crosstalk between CMECs and other cells plays a crucial role in cardiac function (17, 18). Together, targeted CMECs have become a significant prospective therapeutic pathway in the management of CVD.

MiRNAs are a class of noncoding single-strand RNA molecules typically 21–23 nucleotides in length that are encoded by endogenous genes. They have been found to play a regulatory role in gene expression (19). qPCR, in situ hybridization, microarrays, and RNA sequencing are some of the current techniques for miRNA detection (20). Typically, the sequence of miRNA is located within an intron or exon of a noncoding RNA (21). Most genes are transcribed by Pol II to pri-miRNA (22). The pri-miRNA is cleaved in the nucleus by Drosha and DiGeorge syndrome critical region gene 8 (DGCR8) into a pre-miRNA of approximately 70 nucleotides long (23). The pre-miRNA is transported into the cytoplasm via XPO5 and ras-associated nuclear protein (RAN), which is cleaved by Dicer into multiple double-strand miRNAs (24). After the original structure is restored in the Argonaute protein, single-strand mature miRNA is generated by eliminating the passenger strand of the miRNA double-strand body (22).

The mode of action of miRNAs is usually through the base pairing of several nucleotide sites of the miRNA with the untranslated region of the target mRNA, which in turn inhibits the expression of the target mRNA. Particularly crucial to the suppression of mRNA expression are nucleotide 2–8 sites (25). Target prediction often relies on the nucleotides in this region of the binding site (25, 26).

A single miRNA can control the expression of multiple target mRNAs, and a single mRNA can also be regulated by multiple miRNAs. Thus, miRNAs are generally considered promising for their potent and diverse therapeutic functional effects as well as their ability to affect multiple target genes (27). MiRNAs are critical regulators of organism development, cell differentiation, metabolism, and apoptosis (24). Clinical therapeutic strategies targeting miRNAs are already being implemented. For example, clinical study has shown that therapeutic measures targeting miRNAs in viral hepatitis C are efficacious and well tolerated (28). Beg et al. found that miRNA-43 mimics showed considerable potential for the treatment of patients with advanced cancer in phase I clinical studies (29).

MiRNAs can regulate necrotic apoptosis (30). Necrotizing apoptosis in cardiac myocytes in patients with heart disease is usually regulated by miRNAs, which in turn increases or decreases infarct size (31). For example, the hearts of pre-miR-223 knock-out mouse are more vulnerable to ischemia reperfusion (IR) injury. MiR-873 can reduce the infarct size of heart in mice with coronary artery occlusion and reperfusion by inhibiting the necrotic death of cardiomyocytes (31, 32). Although few clinical trials focus on miRNAs for CVDs, changes in the levels of particular miRNAs can often be used in the clinic as a marker to evaluate disease severity. MiRNA-133a/b, a myocardial-specific miRNA, maybe a potential target for the therapy of ventricular fibrillation after MI. Several targets associated with miRNA-133 are related to cardiac disease (33). Reduced miRNA-133a/b expression in patients is reportedly a hallmark of the development of ventricular fibrillation after MI in clinical studies (34). Additionally, miRNA-133 plays an important regulatory role in the differentiation of embryonic stem cells to cardiomyocytes (35). Patients with CAD have significantly elevated peripheral blood miRNA-218 levels, which can also be used as one of the criteria to measure the condition. This finding indicates the feasibility of monitoring variations in miRNA levels to measure and predict the progression of disease (36). Meanwhile, miRNA-133 can inhibit angiogenesis in endothelial cells by targeting vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) (37). Cardiac microvascular injury has important implications for cardiac pathological recovery and the maintenance of physiological homeostasis (38). Therefore, this review summarizes the role and mechanism of various miRNAs in CMECs in CVDs. This review can guide the use of miRNA drugs for the clinical treatment of CVDs.

Diabetes mellitus (DM), caused either by deficient insulin secretion or damaged of pancreatic β cell consists of type I and type II DM. Type I DM is an autoimmune disease that affects pancreatic cells and reduces insulin production. Type II DM is a disease caused by the dysfunction or defect of pancreatic β cells, which reduces insulin signaling and secretion from the pancreas (103). Diabetic patients have elevated blood glucose due to islet damage. High intracellular glucose levels usually lead to metabolic abnormalities with a variety of complications, including cardiac microangiopathy (104). Endothelial cells are some of the first cell types to be exposed to hyperglycemia (105). Hyperglycaemia-induced mitochondrial dysfunction and endoplasmic reticulum stress are associated with mechanisms, such as the activation of protein kinase C (PKC), polyol, and hexosamine pathways. Hyperglycaemic lesion also induces ROS accumulation that damages proteins or DNA and modulates intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors (106). In hyperglycemic CMECs, the glycolytic reserve is significantly reduced, and the ability to produce ATP via glycolysis is impaired (107). Additionally, higher ROS levels and oxidative stress brought on by hyperglycemia frequently result in endothelial cell apoptosis, lowering the mRNA levels of oxidative phosphorylation (OXPHOS)-related genes. Thus, diabetes-induced hyperglycemia damages CMECs through oxidative stress, as well as inhibits mitochondrial glycolysis and the ability of OXPHOS to generate ATP. In turn, CMEC proliferation is inhibited, apoptosis is promoted (107–109). Moreover, this damaged CMECs activate PKC, and release inflammatory cytokines and adhesion factors (110, 111).

Clinical research is gradually focusing on targeting miRNAs in the blood of diabetic patients. Studies have shown that diabetic patients with high plasma miRNA-19a expression have less vascular circulating tissue factor (TF) expression (112). TF is a procoagulant factor released by vascular endothelial cells, which are suppressed by miRNA-19a and miRNA-126. TF content in the peripheral blood of type II diabetic patients is also significantly negatively correlated with miRNA-181b (113). We summarize the miRNA of CMEC in diabetes (Table 2).

MiRNAs play an important role in cellular crosstalk, especially in cardiovascular aspects. We summarize the crosstalk mechanisms between other cells in the heart and CMEC (Figure 2).

A single miRNA can have multitargeting effects, so miRNA-targeted therapeutic approaches have recently become a research hotspot with great prospects. For example, miRNA-145 can reduce in-stent restenosis rate via anti-vascular proliferation with no side effects (136). Improving microvascular endothelial dysfunction has also become an important direction for studying CVD treatment. This review summarizes the roles played by numerous significant miRNAs in CMECs and their mechanisms of action, with the aim of providing a theoretical basis for the clinical use of miRNA therapies. This review also elaborates on the role of miRNAs in the crosstalk between CMECs and other cells in the heart and summarizes the mechanisms of action. MiRNAs in diseases are currently being investigated further and are frequently used as diagnostic criteria (36). However, some remaining issues with miRNA therapy need to be resolved, including the requirement for extremely accurate miRNA sequence prediction and a certain number of miRNAs with highly conserved sequences among different organisms. MiRNA-targeted treatment will undoubtedly advance with the improvement in detecting technologies, such as gene sequencing. Furthermore, miRNA therapy has the advantage of multitargeting, which theoretically fits cardiovascular therapies well. This promising future will undoubtedly serve as a catalyst for the development of cardiovascular therapies.