Exploratory study on the inhibitory effect of dihydrotanshinone on RNA-binding protein (HuR) in the treatment of pulmonary heart disease with right ventricular fibrosis
X Yu, Y Huang, S Li, A Shen, J Chang, Y LiAbstract
Background
Cardiac structural remodeling is often associated with fibrosis. Human antigen R (HuR) shuttles between the nucleus and cytoplasm where it regulates various functions, but whether HuR participates in the regulation of fibrosis during right ventricular (RV) remodeling and the specific molecular mechanisms involved remains unclear.
Methods
Using monocrotaline (MCT) as the primary inducer, a pulmonary hypertension (PH)-induced cor pulmonale model (PHRV) was established. ① Immunofluorescence was utilized to detect the expression and distribution of HuR in both PHRV models and right ventricular cardiac fibroblasts (RVCFs). ② Through molecular docking simulations, a monomer of traditional Chinese medicine, dihydrotanshinone I (DHTS) was identified as an inhibitor of HuR. SD rats and PHRV animal models were divided into five groups: Normal Control (NC), NC+DHTS (HuR inhibitor group), MCT (model control), MCT+DHTS-L (low dose HuR inhibitor for model), MCT+DHTS-H (high dose HuR inhibitor for model). The role of HuR inhibitor DHTS in RV dysfunction and RV remodeling in PHRV was evaluated.
Results
(1) Compared with the normal group, the right heart catheterization detected a significant increase in RV systolic pressure in the model group; pathological staining showed that the RV volume was markedly expanded, the RV wall thickened, RV fibrosis occurred, and right ventricular myocyte hypertrophy was evident in the model group rats, confirming the successful establishment of the PHRV model. (2) Immunofluorescence detection of HuR expression and distribution in the RV of PHRV rats revealed a significant increase in HuR expression two weeks after MCT induction, with HuR aggregating in some tissue areas by four weeks. Further extraction of RVCFs from the PHRV model and examination of HuR expression and distribution in RVCFs showed increased HuR expression in RVFBs of PHRV rats accompanied by increased cytoplasmic distribution. (3) Administration of HuR inhibitor DHTS to the PHRV model group led to increases in PAT, PAT/PET, and TAPSE compared to the control group, along with a thinning of RVFW and a significant reduction in RVSP, suggesting relief of right heart volume load status and RV remodeling. Further H&E, Masson, and wheat germ agglutinin (WGA) staining of heart sections showed that HuR inhibitors significantly improved RV wall thickening, tissue fibrosis, and cardiomyocyte hypertrophy in PHRV rats.
Conclusion
Through the successful establishment of a PHRV rat model and the extraction of RVCFs from PH model rats, it was found that DHTS acts as an inhibitor of HuR. DHTS can alleviate RV dysfunction caused by PH and improve RV hypertrophy and fibrosis. These findings provide scientific evidence for the development of HuR-targeted monomers or small molecule inhibitors from traditional Chinese medicine against right heart fibrosis, presenting significant translational potential.Effect of HuR inhibitorFor image description, please refer to the figure legend and surrounding text.