Inhibition of the mevalonate pathway improves myocardial fibrosis

Abstract

The mevalonate (MVA) pathway serves an important role in ventricular remodeling. Targeting the MVA pathway has protective effects against myocardial fibrosis. The present study aimed to investigate the mechanism behind these effects. Primary cultured cardiac fibroblasts from C57BL/6 mice were treated in vitro in 5 groups: i) negative control; ii) angiotensin II (Ang II) model (1x10-5 mol/l); iii) Ang II + rosuvastatin (ROS); iv) Ang II + alendronate (ALE); and v) Ang II + fasudil (FAS). Collagen and crystal violet staining were used to assess morphological changes in cardiac fibroblasts. Reverse transcription quantitative PCR and western blotting were used to analyze the expression of key signaling molecules involved in the MVA pathway. Collagen staining in the ALE, FAS, and ROS groups was weak compared with the Ang II group, while the rate of cell proliferation in the ROS, ALE, and FAS groups was slower compared with that in the Ang II group. In addition, the expression of key signaling molecules in the MVA pathway, including transforming growth factor-β1 (TGF-β1), heat shock protein 47 (HSP47), collagen type I α1 (COL1A1), vascular endothelial growth factor 2 (VEGF2) and fibroblast growth factor 2 (FGF2), was decreased in the FAS and ROS groups compared with the Ang II model. Compared with the Ang II group, 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR) gene expression was significantly lowered in the drug intervention groups, whereas farnesyl pyrophosphate synthase (FDPS) expression was downregulated in the ALE group, but elevated in the FAS and ROS groups. Compared with that in the Ang II group, ras homolog family member A (RhoA) expression was downregulated in the FAS and ROS groups, whilst mevalonate kinase expression was reduced in the ROS group. Protein expression of TGF-β1, COL1A1 and HSP47 were decreased following intervention with each of the three drugs compared with the Ang II group. Overall, rosuvastatin, aledronate and fasudil decreased the proliferation of myocardial fibroblasts and inhibited collagen synthesis. Rosuvastatin had the strongest protective effects against myocardial fibrosis compared with the other drugs tested, suggesting this to be a potential agent for the clinical treatment of cardiovascular disease.

Epigenetic and Genetic Mechanisms Underlying Cardiovascular Diseases and Neurodevelopmental Disorders

“…The dynamic regulation of m 6 A affects the expression level of specific genes involved in PAH. In addition, inflammation and immune disorders are also involved in pulmonary vascular remodeling, especially through the secretion of cytokines and metabolic reprogramming (Xu et al, 2021). The pathological specimens of PAH patients showed the accumulation of perivascular inflammatory cells, such as macrophages, lymphocytes, and mast cells (Jia et al, 2020).…”

“…Recent studies have found that the occurrence and development of PAH is the result of a variety of cell interactions, which is not only related to PAECs dysfunction, PASMCs phenotypic switching and fibroblast activation, moreover, it is also closely related to the immune microenvironment imbalance. Accumulating evidence suggests that inflammation is a major contributor to vascular remodeling in PAH (Xu et al, 2021). The disorder of the immune microenvironment plays an important role in the development of PAH, and the immune system regulates PAH via multiple mechanisms.…”

“…Studies have shown that lactate is a powerful amplifier of inflammation in arthritis (Souto-Carneiro et al, 2020). In PAH, an altered immune system contributes significantly to pulmonary vascular remodelling by promoting inflammatory cell recruitment and autoimmune dysfunction (Xu et al, 2021).…”

Se alleviates homocysteine‑induced fibrosis in cardiac fibroblasts via downregulation of lncRNA MEG3

“…Cardiovascular diseases represent the leading causes of mortality worldwide (27). Almost all cardiovascular diseases are related to the pathological myocardial remodeling process that is characterized by tissue fibrosis (28)(29)(30). It is therefore crucial to clarify the specific molecular mechanism of cardiac fibrosis and to determine some targets for the treatment of cardiovascular diseases.…”

Use of Statins in Heart Failure with Preserved Ejection Fraction: Current Evidence and Perspectives

“…Statins may also reduce myocardial fibrosis, presumably via the inhibition of Rho proteins and increased NO bioavailability [119]. Statins were superior to other drugs blocking the activity of the mevalonate pathway (alendronate and fasudil) in their effects on the proliferation of myocardial fibroblasts and inhibited collagen synthesis in vitro [120]. In vitro studies have shown the ability of statins to prevent the differentiation of fibroblasts into myofibroblasts [121] and to induce the reverse differentiation of profibrotic myofibroblasts through the inhibition of GGPP [122], which abrogates a key process in myocardial fibrosis.…”