Betulinic acid prevents high glucose-induced expression of extracellular matrix protein in cardiac fibroblasts by inhibiting the TGF-β1/Smad signaling pathway

Abstract

The proliferation and differentiation of cardiac fibroblasts (CFs) is central to cardiac fibrosis. Betulinic acid (BA) is an active compound isolated from the bark of the birch tree Betula spp. (Betulaceae) and has been shown to attenuate hepatic fibrosis. However, the effect of BA on the high glucose‑induced fibrosis response in CFs remains to be elucidated, therefore, the present study investigated the effect of BA on high glucose‑induced CFs and examined the possible mechanism underlying the effect of BA on CF transdifferentiation. CFs were pre‑incubated with various concentrations of BA for 24 h and then stimulated with high glucose (25 mM) for various times. Cell proliferation was evaluated using an MTT assay. The mRNA expression levels of α‑smooth muscle actin (SMA) and transforming growth factor (TGF)‑β1 were determined using reverse transcription‑quantitative polymerase chain reaction analysis. The protein expression levels of α‑SMA, collagen I, collagen III, fibronectin, TGF‑β1, small mothers against decapentaplegic (Smad)2/3, phosphorylated (p)‑Smad2 and p‑Smad3 and were detected using western blot analysis. The data revealed that BA attenuated the CF proliferation and myofibroblast differentiation induced by high glucose. In addition, BA inhibited the expression of extracellular matrix (ECM) in the CFs induced by high glucose. It was also found that BA inhibited the high glucose‑induced phosphorylation of Smad2/3 in the CFs. Taken together, BA suppressed the high glucose‑induced increase in the proliferation of CFs and expression of ECM via inhibition of the TGF‑β1/Smad signaling pathway. Thus, BA may offer therapeutic potential towards the treatment of cardiac fibrosis.

Betulinic acid shows anticancer activity against equine melanoma cells and permeates isolated equine skin in vitro

“…However, the results show that normal equine dermal fibroblasts are also sensitive to BA in the concentrations investigated. These observations are in agreement with previously reported low selectivity indices of BA for normal human dermal fibroblasts [46,47] and attenuated high glucose-induced proliferation of human cardiac fibroblasts after treatment with BA [48]. But they are in contrast to findings in other human normal cells, such as melanocytes, dermal fibroblasts and peripheral blood lymphocytes, which revealed to be more resistant to a BA treatment than cancer cells [5,20,21].…”

Betulinic Acid Improves Cardiac-Renal Dysfunction Caused by Hypertrophy through Calcineurin-NFATc3 Signaling

“…To induce LV hypertrophy, ISO was used in the present study. ISO caused to LV hypertrophy and chronic stimulation in β-adrenergic receptor by injecting isoprenaline induced cardiac fibrosis [12]. In Figure 3, picrosirius red staining showed that BA attenuated cardiac fibrosis in ISO-induced cardiac hypertrophy.…”

“…Treatment with BA reduced heart weight and left ventricle weight in ISO-induced cardiac hypertrophy, and also improved heart function and cardiac fibrosis. ISO was used in our study because it is known to induce left ventricular hypertrophy and chronic stimulation at β-adrenergic receptors, leading to cardiac hypertrophy and cardiac fibrosis [12]. Cardiac hypertrophy markers, such as ANP, BNP and β-MHC were decreased in the BA treatment group, especially in the high-concentration BA group.…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

“…Moreover, BA can prevent cardiac fibrosis, characterized by the increased proliferation of cardiac fibroblasts and accumulation of extracellular matrix proteins, which can further contribute to the pathogenesis of myocardial infarction. At the molecular level, BA inhibited the glucose-induced expression of extracellular matrix proteins such as α-SMA, collagen, and fibronectin through the inhibition of the TGF-β1/Smad signaling pathway [ 70 ].…”