Protective effect of curcumin on exercise-induced myocardial fibrosis in rats
Myocardial fibrosis (MF) is a pathological process characterized by excessive deposition of extracellular matrix (ECM) and imbalanced collagen composition after myocardial injury. It is closely related to various heart diseases such as myocardial infarction, chronic heart failure, and atrial fibrillation. Research has shown that excessive physiological stress can trigger inflammatory reactions in myocardial tissue, leading to myocardial fibrosis and myocardial injury. P38 MAPK, a member of the mitogen activated protein kinases (MAPKs) family, can be activated under pathological or physiological stress by phosphorylating mitogen and stress activated protein kinase 1 (MSK1) to activate nuclear factor kappa-B (NF – κ B). NF – κ B is the main regulatory factor of inflammatory response, composed of homologous and heterologous NF – κ B/Rel protein dimers. After activation, it enters the nucleus and induces transforming growth factor – β 1 (TGF – β 1) and tumor necrosis factor – β 1 (TNF – β 1). The expression of pro-inflammatory factors such as tumor necrosis factor – α (TNF – α) and interleukin-1 β (IL-1 β), among which TGF – β 1 is the main inducer of muscle tissue fibrosis in the body. Curcumin is a bioactive component extracted from the perennial plant turmeric, which has various physiological and pharmacological activities such as antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. Previous research by the research team has confirmed that curcumin intervention during training can delay and inhibit oxidative stress and exercise-induced myocardial injury induced by excessive exercise stress. At the same time, it can effectively suppress the inflammatory response induced by excessive exercise stress, downregulate the content of pro-inflammatory factors such as TGF – β 1, improve exercise-induced renal fibrosis, and protect renal function/structure. This study established an animal model of long-term, high-intensity exercise induced exercise-induced organ injury using 6-week incremental load treadmill training. The aim was to investigate the mechanism by which curcumin regulates the activation and expression of p38 MAPK/NF – κ B signaling pathway related proteins, inhibits the synthesis of inflammatory factors in myocardial tissue, alleviates excessive deposition of myocardial ECM caused by long-term, high-intensity exercise, and improves myocardial fibrosis.

 

Long term and excessive exercise stress causes the heart to maintain a high cardiac output for a long time. Prolonged excessive ventricular dilation leads to myocardial fibrosis and gradually develops into chronic myocardial injury, significantly increasing the risk of arrhythmia. Breuckmann et al. found that marathon sports lovers have a high incidence rate of myocardial fibrosis by using the delayed gadolinium enhancement technology of magnetic resonance, which is prone to myocardial injury in ordinary people. Rao found that long-term and high-intensity exercise induced myocardial injury in rats, and excessive exercise stress disrupted the dynamic balance between the synthesis and degradation of ECM in myocardial tissue. ECM deposition intensified, inducing myocardial fibrosis. At the same time, the concentration of cTnI, a marker of myocardial injury in the blood center, increased, leading to abnormalities in cardiac function/tissue morphology/ultrastructure. Weight changes can reflect the impact of exercise intensity on the body. The results of this study showed that the model group rats consumed a large amount of energy and substance due to training intensity exceeding the body’s ability to withstand exercise load, resulting in a significant decrease in body weight compared to the control group. At the same time, the myocardial glycogen volume fraction increased, and the serum cTNI content significantly increased. Pathological changes also occurred in the morphology and ultrastructure of myocardial tissue. The 6-week treadmill incremental load training program adopted in this study resulted in excessive ECM deposition and reactive myocardial fibrosis in rat myocardial tissue due to excessive exercise stress, leading to myocardial function/structural damage. The above results are consistent with previous research findings.
The cumulative effect of chronic inflammatory response can trigger myocardial fibrosis. The main member of the MAPKs family, p38 MAPK, can regulate the expression of related genes or protein synthesis at the transcriptional or translational level, and play an important role in stress responses such as inflammation and cell apoptosis. Aschar Sobi et al. found that after 6 weeks of high-intensity exercise training in mice, the expression of p38 MAPK increased, macrophage infiltration appeared in the mouse atria, the expression of inflammatory factors TNF – α and IL-1 β increased, and myocardial fibrosis occurred. At the same time, after intervention with p38 MAPK inhibitors, exercise induced atrial fibrillation and fibrosis were inhibited. NF – κ B, as a rapidly inducible transcription factor, plays a major role in the inflammatory response of the body, regulating the expression of inflammatory factors such as TGF – β 1 and TNF – α. Stambe et al. found that blocking p38 MAPK activation can effectively inhibit inflammatory damage in renal tissue. TGF – β 1 is the main inducer of myocardial fibrosis, and overexpression can disrupt the balance between ECM synthesis and degradation in myocardial tissue. Firstly, it induces the formation of smad complexes in the human nucleus, regulates the activation of target genes in fibroblasts, synthesizes a large amount of ECM components such as collagen, and leads to excessive ECM deposition By enhancing the expression of TIMP-1 and inhibiting the activity of MMP, ECM degradation is reduced. Turmeric has a wide range of effects and is often used as a spice, food additive, and herb. Curcumin, as a bioactive polyphenol extract from turmeric, has health benefits mainly in inhibiting inflammation and antioxidation. The results of this study showed that compared with the control group, the p38 MAPK and p-p38 MAPK/p38 MAPK in the myocardial tissue of the model group rats did not show significant changes, but showed an upward trend. However, the protein expression of p-p38 MAPK and NF – κ B p65 significantly increased, and the content of myocardial fibrosis factor TGF – β 1 and related inflammatory factors increased, leading to excessive deposition of myocardial ECM; After intervention with curcumin during the training process, compared with the model group, there was no significant change in p38 MAPK and p-p38 MAPK/p38 MAPK in rat myocardium, but they showed a downward trend. The protein expression of p-p38 MAPK and NF – κ B p65 was significantly down regulated, and the content of TGF – β 1 and related inflammatory factors decreased accordingly. The deposition of myocardial ECM was alleviated; At the same time, cardiac function, tissue morphology, and ultrastructure have all been effectively improved. Topcu Tarladacalisir et al. found that after intervention with curcumin in ulcerative colitis model rats, the phosphorylation level of p38 MAPK decreased, the immune response characteristics of MAPKs were restored, and inflammation and lipid peroxidation were alleviated. Our previous research has confirmed that curcumin can effectively inhibit the renal inflammatory response caused by excessive exercise stress in rats, downregulate the levels of pro-inflammatory factors such as TGF – β 1, and restore the balance between ECM synthesis and degradation. In summary, supplementing curcumin during long-term high-intensity training can effectively block the occurrence and development of exercise-induced myocardial fibrosis. Its possible mechanism is that curcumin inhibits the excessive activation of p38 MAPK in myocardial tissue, downregulates the protein expression of NF – κ B p65, reduces the synthesis and secretion of inflammatory factors, especially TGF – β 1, which induces myocardial fibrosis, improves the balance between ECM synthesis and degradation, and alleviates myocardial fibrosis.
From this, it can be seen that curcumin can effectively inhibit the inflammatory response of myocarditis in long-term and high-intensity exercise rats by regulating the p38 MAPK/NF – κ B signaling pathway, alleviate myocardial fibrosis, and protect cardiac structure/function.