Central venous catheters (CVCs) are extensively applied in medical and health institutions. CVCs can offer safe and reliable venous access to tumour chemotherapy, parenteral nutrition, long-term infusion and treatment of critically ill patients [1]. After intravenous catheterisation, the catheter punctures the vascular wall, resulting in endothelial cell injury and hemodynamic changes and further promoting blood hypercoagulability [2]. Hence, catheter-related complications are inevitable, amongst which catheter-related thrombosis (CRT) is the most severe, resulting in pulmonary embolism, recurrent deep vein thrombosis (DVT), post-thrombotic syndrome and sepsis [3]. Recent studies noted that 16–18% of patients with CVCs have evidence of CRT as revealed by ultrasound or intravenous screening [4]. Moreover, the incidence of asymptomatic CRT is reportedly as high as 68% [5]. CRT cannot be detected without ultrasonic evaluation and testing, and compounding this problem is the fact that only 1–5% of patients are symptomatic [6]. Therefore, CRT can be characterised as a ‘high risk, common’ disease. CRT can increase pain sensitivity, leading to catheter dysfunction, increased risks of infection and central venous stenosis; moreover, it increases the length of hospital stay and medical costs [7]. Therefore, CRT prevention is necessary.

The Infusion Nurse Society, following the amendments of the Infusion Practice Standard of 2016, has encouraged patients undergoing infusion to engage in physical activity and exercise as early as possible to prevent CRT formation [8]. Colwell et al. [9] found no statistically significant differences between anti-coagulant drugs and physical exercise in terms of reducing DVT incidence. Compared with anti-coagulant drugs, physical activity can effectively minimise or eliminate the risk of bleeding. Aerobic exercise and resistance exercise on the side of catheterisation can benefit the increase in blood flow velocity of the heart and blood vessels [10]. Early resistance exercises can increase muscle strength and enhance subendocardial blood perfusion by increasing cardiac pressure load to achieve the optimal balance between cardiovascular oxygen supply and demand and improve cardiovascular functions [11].

MiRNAs are a class of endogenous non-coding small RNA molecules that play an important regulatory role in angiogenesis [12]. Members of the miR-17-92 cluster have a considerable influence on the cardiovascular system. Specifically, miR-92a regulates vascular dynamic balance by upregulating the expression of endothelial pro-inflammatory factors [13, 14]. Micro-92a-3p is reported to be involved in regulating vascular system dysfunction and mediating blood flow shear stress, and its expression is up-regulated in a rat model of DVT [15, 16].

When the vessel wall is punctured by a catheter, oxidative stress damages vascular endothelial cells, leading to ROS and reactive nitrogen over-production and eventually disrupting the redox balance [17]. A high ROS content can increase the level of malondialdehyde (MDA), further causing oxidative stress-induced tissue damage, increasing membrane permeability and rupturing the double-layered structure of the cell membrane [18]. HO-1 (HMOX1), an antioxidant enzyme found in vascular endothelial cells and smooth muscle cells, can protect damaged blood vessels via inhibiting the proliferation of vascular smooth muscle cells [19].

Pro-apoptotic pathways (i.e. mitogen-activated protein kinases [MAPKs]) and inflammatory response pathways (i.e. NF-κB) are important in regulating apoptosis and tissue damage. A sustained increase in ROS can promote endothelial cell apoptosis and activate inflammatory responses through the activation of the MAPK and NF-κB signalling pathways [20]. In vivo experiments have shown that MAPK regulates Ace2 mRNA expression in the aortic vascular smooth muscle cells of rats, indicating that MAPKs may play a role in repairing vascular endothelial injury [21]. However, the signalling pathway that initiates CRT-induced oxidative stress injury in rats remains unclear. Gan's research [22] shows that HO-1 may be the target of miR-92a-3p and p38 MAPK/NF-κB pathway. miR-92a-3p may regulate HO-1/p38 MAPK/NF-κB pathway and result in CRT. Oxidative stress may activate MAPK/NF-κB, mediate endothelial cell apoptosis, promote the expression of tissue factor and platelet secretion, and regulate venous thrombosis.

Resistance exercise is a form of intervention that has been repeatedly validated to reduce the risk of cardiovascular diseases [23]. However, the underlying molecular mechanism by which resistance exercises regulate CRT occurrence has not been elucidated yet. This study investigated the effect of resistance exercise on CRT-induced thrombosis formation. Mechanistically, resistance exercise mitigated oxidative stress and inflammation via regulating miR-92a-3p expression and the MAPK/NF-κB pathway.

The incidence of thrombosis is the highest amongst all diseases, and its incidence rate is increasing. Through resistance exercise intervention, this study investigated the mechanism by which oxidative stress and miR-92a-3p prevent CRT in rats. Results showed that blood flow direction and velocity changed after catheter implantation, resulting in thrombosis formation, increased ROS production and MDA activity, decreased HO-1 level and increased miR-92a-3p expression. CRT also increased the release of pro-inflammatory cytokines, activated the P38MAPK/NF-κB P65 pathway and inhibited IκBa expression. Oxidative stress refers to excess ROS produced by the body when it is adversely stimulated, resulting in an imbalance between oxidative and antioxidant systems, which in turn leads to the accumulation of free radicals in cells and cell damage [27]. ROS content is an important marker of oxidative stress injury and one of the important factors leading to thrombosis occurrence and development [28]. In the cardiovascular system, ROS plays a role in controlling inflammation, proliferation, apoptosis, endothelial function and angiogenesis [29]. Aizawa et al. [28] demonstrated that an increase in ROS production in endothelial cells can promote thrombosis formation, leading to endothelial cell dysfunction. High ROS contents can convert polyunsaturated fatty acids on the cell membrane and produce MDA, further causing oxidative stress-induced tissue damage, increasing membrane permeability and rupturing the double-layered structure of the membrane.

Most miRNAs are effective therapeutic targets for cancer, but their roles in the cardiovascular system are not entirely clear [30]. As a member of the miR-17-92 family (i.e. miR-17, -18a, -19a/B, -20A and miR -92a), miR-92a-3p is highly expressed in vascular endothelial cells and participates in the regulation of vascular endothelial functions [31‐33]. A sharp decrease in blood flow shear stress after catheter placement in the external jugular vein leads to the up-regulation of miR-92a-3p expression, vascular endothelial cell proliferation, apoptosis and thrombogenic molecular secretion and CRT formation [34]. As a member of the HO protein family, HO-1 is a common mammalian induction enzyme that degrades oxyhaemoglobin and produces antioxidants to protect cells from oxidative stress damage [35].

Pro-apoptotic pathways (e.g. MAPKs) and inflammatory response pathways (e.g. NF-κB) are important in regulating apoptosis and tissue damage. MAPKs and NF-κB are sensitive ROS signalling pathways. A sustained increase in ROS production can promote endothelial cell apoptosis and activate inflammatory responses [20]. NF-κB is maintained in its inactive form in the cytoplasm by binding to an inhibitory protein of the IκB family. In turn, this protein is phosphorylated and degraded under inflammatory stimuli, allowing the transfer of NF-κB p65 subunit phosphorylation and NF-κB dimer to the nucleus [36]. Punctures or long-term catheter placement in the vascular wall can cause oxidative stress injury in vascular endothelial cells. Moreover, they affect the biological functions of endothelial cells, suggesting that CRT and OS injury are closely linked to each other, which is consistent with the CRT model in the present study. Numerous studies confirmed that upper limb exercises can effectively promote blood circulation and reduce CRT occurrence [37]. In the current study, the resistance exercise intervention conducted for 8 weeks reduced ROS production and MDA activity, increased HO-1 level and down-regulated miR-92a-3p expression. Furthermore, the intervention reduced the P38MAPK/NF-κB P65 pathway and their phosphorylation levels and activated IκBa expression.

Thrombosis is a disease that involves numerous factors and systems. Histological features of thrombosis were explored in this study. In the control, Sham and Sham + RE groups, smooth and intact venous endothelial cells were observed under an optical microscope, and no thrombosis was found in the vascular lumen. Small amounts of powder were observed in the lumen of the rats in the Sham + RE group, but no thrombosis was observed. In the CRT group, inflammatory cells infiltrated around the vessel wall and formed a thrombus, and no endothelial cells were present at the adhesion site. In the CRT + RE group, a small number of red blood cells, white blood cells and platelet beams gathered in the lumen, and the severity of thrombus was less than that in the CRT group. The CRT in the CRT group was observed at the edge of the catheter. Trabecular platelets, red blood cells and white blood cells were found in the thrombus. Thus, clinical treatment of CRT remains a difficult task for clinicians. Anticoagulants [38], catheter surface coating [39], compression therapy [40] and grip strength training are commonly used in clinical settings [4]. Resistance exercise, also known as resistance training or strength training, usually refers to the process by which the body overcomes resistance to achieve muscle growth and increased strength [8]. Clinical grip strength training is a kind of resistance exercise training. Resistance exercises up-regulate the antioxidant defence system, decrease the concentration of cellular ROS and confer protection against oxidative stress-related diseases. The present study also proved that anti-resistance exercises changed blood flow shear stress, inhibited endothelial cells to repair oxidative stress and reduced ROS production, thereby improving the function of vascular endothelium and, to a certain extent, playing a role in preventing venous thrombosis [41, 42]. These results were consistent with the findings of Quinteiro [43].

By monitoring changes in miRNA expression, researchers found that miRNA circulation also changes as the intensity of resistance exercises increases [44, 45]. The current study showed that the resistance exercise intervention down-regulated miR-92a-3p expression, affected endothelial cell expression, repaired oxidative stress damage and inhibited CRT formation. Enhancing HO-1 activity by inhibiting the action of miR-92a can reduce oxidative stress damage and improve endothelial functions [34]. Intravenous up-regulation of miR-92a induces oxidative stress in endothelial cells, leading to endothelial inflammation and dysfunction [29]. We speculated that miR-92a-3p and HO-1 have a certain correlation with CRT. The results showed that miR-92a-3p was positively correlated with HO-1. However, the target of HO-1 regulation of thrombosis was not comprehensively explored. Therefore, the supposition that resistance exercise may mediate the targeting of HMOX1 by miR-92a-3p to regulate oxidative stress and prevent CRT occurrence warrants further experimental verification.

Shear stress is also a strong inducer of HMOX1 that can inhibit leukocyte adhesion and platelet aggregation. HO-1 can inhibit the formation of venous thrombosis by alleviating oxidative stress mechanisms [46]. However, the role of HO-1 in reducing tissue damage, especially in venous thrombosis, through its antioxidant activity is poorly understood. Recent studies explored potential therapeutic tools for manipulating apoptosis, inflammation and oxidative stress to improve the outcome of vascular diseases. Studies of the HO-1 promoter region revealed that the combination of the presence of transcriptional response elements, including activator protein I, activator protein II, NF-κB and interleukin-6 response elements, with anti-oxidant response elements, induces the inhibition of the proliferation of vascular smooth muscle cells [47]. Aside from the fact that HO-1 expression is induced by oxidative stress, HO-1 also plays an important cellular protective role in various inflammatory diseases. Previous studies explored the mechanism of oxidative stress in rat brain as a function of age. Western blot and immunohistochemistry analyses revealed that the expression of the HO-1 protein in the heart antioxidant enzyme slightly decreased [48], whereas that in the kidney slightly increased. However, HO-1 expression in the kidney substantially decreased by the fifth week [49]. Therefore, HO-1 expression is slightly different in varying tissues and at various time points. Nevertheless, HO-1 was undeniably structurally up-regulated amongst the top climbers, and the high HO-1 expression level was maintained months after reaching the peak [50]. Eight weeks of climbing resistance training induced an increase in HO-1 expression, which led to an antioxidant reaction in the blood vessels and initiated the corresponding protective mechanism.

Vascular catheterisation resulted in endothelial cell oxidative stress damage and miR-92a-3p-mediated inflammation, ultimately leading to thrombosis. Resistance exercise intervention accelerated blood flow speed, repaired oxidative stress damage, reduced ROS production and decreased CRT incidence, thereby improving cardiovascular functions. Hence, resistance exercises are important in the prevention and treatment of CRT. Resistance exercise may mediate the regulation of oxidative stress by targeting HMOX1 via miR-92a-3p to prevent CRT occurrence. However, this supposition warrants further research. Resistance exercise intervention provides a strong theoretical basis and research direction for the prevention and treatment of CRT.