Study on the protective effect of earthworm extract on pathological myocardial hypertrophy rats based on Akt/mTOR/NF – κ B signaling pathway
Pathological myocardial hypertrophy is an adaptive response of the heart to pathological stimuli such as overload. When the cardiac pressure is overloaded, myocardial cells are unable to proliferate to support the increased demand, and compensatory hypertrophy of the left ventricle is necessary to maintain cardiac output. Persistent myocardial hypertrophy ultimately leads to heart failure or even sudden death. Medicinal earthworms (Lumbricus or Earthworm), also known as earthworms, are the dried bodies of the giant earthworm family, such as the Eisenia fetida or the striped earthworm. They contain active ingredients such as peptides, amino acids, nucleotides, and protein compounds, and have various pharmacological activities such as anti-inflammatory, anti fibrotic, and regulating cell apoptosis. The preliminary research of the research group found that Lumbricus can lower blood pressure by reducing Ang II and inhibiting the activity of angiotensin-converting enzyme. However, the role and mechanism of Lumbricus in pressure induced pathological myocardial hypertrophy are still unclear.
The protein kinase B/mammalian rapamycin target protein (Akt/mTOR) signaling pathway is involved in cell proliferation, differentiation, and apoptosis at multiple levels and targets. It can affect the development of pathological myocardial hypertrophy by anti-inflammatory and regulating energy metabolism, and is an important target for drug regulation of pathological myocardial hypertrophy. In addition, the nuclear factor kappa B (NF – κ B) signal that activates B cells is an important nuclear transcription factor that can control cell proliferation, innate and adaptive immunity, inflammation, and cell apoptosis. It also participates in the biological processes of early immune response and various stages of inflammation. In the development of myocardial hypertrophy, sustained activation of Akt/mTOR and NF – κ B upregulates the expression of inflammatory factors and promotes chronic inflammation of the heart. However, there is currently no report on whether earthworms can exert a protective effect on myocardial hypertrophy by regulating the Akt/mTOR/NF – κ B signaling pathway. This study used earthworm extract to intervene in the pathological myocardial hypertrophy model induced by abdominal aortic coarctation (AAC), and explored the effect and mechanism of earthworm on pathological myocardial hypertrophy.

 

 

Earthworm has played a significant role in the treatment of hypertension, diabetes and other aspects with its natural anti-inflammatory, anti fibrosis, apoptosis regulation and other characteristics. Pathological myocardial hypertrophy is a high-risk factor for the occurrence and development of cardiovascular diseases, and is a common pathological process of various cardiovascular diseases; Persistent pathological myocardial hypertrophy triggers severe myocardial remodeling, leading to heart failure, sudden death, etc. In recent years, a large number of studies have shown that traditional Chinese medicine extracts have significant protective effects in the occurrence and development of cardiovascular diseases. The research team has found in previous studies that earthworms may lower blood pressure by reducing Ang II and inhibiting angiotensin-converting enzyme activity. This study further investigated the role and mechanism of earthworm extract in the pathological myocardial hypertrophy model induced by AAC. Therefore, this study used the classic AAC method to establish a pathological myocardial hypertrophy model, with Captopril as the positive control.

Pathological myocardial hypertrophy is mainly characterized by hypertrophy of myocardial cells, upregulation of embryonic gene expression, and enhanced inflammatory response. Consistent with previous research reports, the results of this study showed that the AAC model group of rats had impaired cardiac function, decreased EF and FS values, and significantly increased heart mass indices HW, HW/BW, and LVW/BW. Furthermore, histopathological staining results showed that AAC led to an increase in the cross-sectional area of myocardial cells and a significant increase in the expression of genes related to myocardial hypertrophy, such as ANP, BNP, and β – MHC. This indicates that AAC successfully induced pathological myocardial hypertrophy in rats. Interestingly, this study found that after treatment with earthworm extract, the cardiac contractile function of rats was significantly improved, and the increase in heart mass index and histological changes induced by AAC were significantly inhibited. The markers of myocardial hypertrophy were also restored to normal levels, and the therapeutic effect of low-dose earthworm was better than that of Captopril, indicating that earthworm extract can inhibit AAC induced pathological myocardial hypertrophy. In addition, inflammation is also involved in the occurrence and development of pathological myocardial hypertrophy, and pro-inflammatory factors IL-6 and TNF – α play important roles in the inflammatory response of myocarditis. In this study, AAC induced a myocarditis response, with significantly increased levels of IL-6 and TNF – α mRNA expression. However, treatment with earthworm extract could almost restore the expression of inflammatory factors to normal levels, and the therapeutic effect was comparable to that of Captopril, suggesting that earthworm extract can inhibit inflammatory response and improve AAC induced myocardial hypertrophy.

Numerous studies have found that the Akt/mTOR/NF – κ B signaling pathway plays an important role in the occurrence and development of pathological myocardial hypertrophy, and overexpression of cardiac cell specific Akt and mTOR may lead to myocardial hypertrophy. NF – κ B is stimulated by various factors in pathological myocardial hypertrophy and can activate various inflammatory factors such as TNF – α and IL-6. The results of this study showed that the degree of myocardial hypertrophy and the inflammatory response of myocarditis were significantly increased in AAC rats. However, in the Akt/mTOR signaling pathway, the expression of p-Akt and p-mTOR proteins in the earthworm treatment group was significantly lower than that in the model group. In the NF – κ B signaling pathway, the expression level of p-NF – κ B p65 decreases, but the expression level of I κ B significantly increases. Therefore, the Akt/mTOR/NF – κ B signaling pathway may be inhibited during the treatment of pathological myocardial hypertrophy with earthworm. In addition, earthworm extract can also inhibit the upregulation of phosphorylated protein expression of Akt, mTOR, and NF – κ B p65 in PE induced hypertrophic cardiomyocytes. It can be seen that the extract of Lumbricus may exert a protective effect in pathological myocardial hypertrophy by inhibiting the Akt/mTOR/NF – κ B signaling pathway, but the specific cascade reactions and targets need further research.

In summary, this study found for the first time that Lumbricus has a certain protective effect on pathological myocardial hypertrophy induced by pressure load. Its mechanism may be related to the inhibition of AAC induced myocardial hypertrophy and myocarditis, and it exerts its effect through the Akt/mTOR/NF – κ B signaling pathway. This study provides experimental evidence for the further clinical application of Lumbricus, as well as new ideas for the prevention and treatment of pathological myocardial hypertrophy and heart failure. However, the primary structure of the effective components in inhibiting pathological myocardial hypertrophy in Lumbricus has not been elucidated and further research is needed. This project will further explore the effective ingredients and mechanisms of action of Lumbricus in preventing and treating heart failure.