Alpha Mangostin Derived from <i>Garcinia magostana</i> Linn Ameliorates Cardiomyocyte Hypertrophy and Fibroblast Phenotypes <i>in Vitro</i>

Abstract

Cardiac hypertrophy and fibrosis are significant risk factors for chronic heart failure (HF). Since pharmacotherapy agents targeting these processes have not been established, we investigated the effect of alphamagostin (α-man) on cardiomyocyte hypertrophy and fibrosis in vitro. Primary cultured cardiomyocytes and cardiac fibroblasts were prepared from neonatal rats. After α-man treatment, phenylephrine (PE) and transforming growth factor-beta (TGF-β) were added to the cardiomyocytes and cardiac fibroblasts to induce hypertrophic and fibrotic responses, respectively. Hypertrophic responses were assessed by measuring the cardiomyocyte surface area and hypertrophic gene expression levels. PE-induced phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2, and p38 was examined by Western blotting. Fibrotic responses were assessed by measuring collagen synthesis, fibrotic gene expression levels, and myofibroblast differentiation. In addition, TGF-β-induced reactive oxygen species (ROS) production was investigated. In cultured cardiomyocytes, α-man significantly suppressed PE-induced increases in the cardiomyocyte surface area, and the mRNA levels (atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP)). Treatment with α-man significantly suppressed PE-induced Akt phosphorylation, but not ERK and p38 phosphorylation. In cultured cardiac fibroblasts, α-man significantly suppressed TGF-β-induced increases in L-proline incorporation, mRNA levels (POSTN and alpha-smooth muscle actin (α-SMA)), and myofibroblast differentiation. Additionally, it significantly inhibited TGF-β-induced reduced nicotinamide adenine dinucleotide phosphate oxidase4 (NOX4) expression and ROS production in cardiac fibroblasts. Treatment with α-man significantly ameliorates hypertrophy by inhibiting Akt phosphorylation in cardiomyocytes and fibrosis by inhibiting NOX4-generating ROS in fibroblasts. These findings suggest that α-man is a possible natural product for the prevention of cardiac hypertrophy and fibrosis.

α-Mangostin Inhibits the Activation of Myofibroblasts via Downregulation of Linc-ROR-Mediated TGFB1/Smad Signaling

“…Suppression of TGF-β1/Smad2 signaling was in favor of our finding regarding the downregulation of myofibroblast activities, and these benefits may be due to the inhibition of lincROR by α-mangostin ( Figure 7 ). Our results were in line with various studies showing that α-mangostin inhibited myofibroblast transdifferentiation and TGF-β-induced fibrotic response via suppressing nicotinamide adenine dinucleotide phosphate oxidase4 (NOX4)-generating reactive oxygen species (ROS) or enhancing antioxidant enzymes, leading to the alleviation of the liver [ 32 ], lung [ 30 ] or cardiac fibrosis [ 33 ]. Likewise, α-mangostin was demonstrated to reduce the expression of IL-6 and IL-8 expression in P. gingivalis LPS-stimulated human gingival fibroblasts [ 39 ].…”

“…Moreover, α-mangostin has been demonstrated to reduce the acetaldehyde-induced liver fibrosis by inhibiting myofibroblast transdifferentiation of hepatic stellate cells along with decreased expression of TGF-β and increased anti-oxidant capacity [ 32 ]. Similarly, it markedly suppressed the TGF-β-induced myofibroblast differentiation and oxidative stress in cardiac fibroblasts [ 33 ]. Nevertheless, whether α-mangostin can ameliorate oral fibrogenesis has not been elucidated.…”

Antioxidant α-Mangostin Coated Woven Polycaprolactone Nanofibrous Yarn Scaffold for Cardiac Tissue Repair

“…In addition, proliferation of rBMSCs on the scaffolds were studied and the result interpreted that a significant increase in cell proliferation with time in comparison to PWS was observed due to the nontoxic and healing properties of α-mangostin (Figure c,d). PWS and MPWS provide a three-dimensional environment and high surface area available for the initial contact of cells, along with gap and grooves in the scaffold provided possible infiltration of cells facilitating higher proliferation number. , With regard to the interaction of cardiac cells on the scaffolds, immunofluorescence staining studies of connexin43 and α-sarcomeric actin showed alignment of the cellular cytoskeleton in the direction of the nanofiber yarns in both PWS and MPWS with increased expression observed in α-mangostin coated scaffolds due its cardioprotective properties reported to prevent degeneration of myocardial tissues by inhibition of oxidative stress. , Furthermore, the functionality of cells by beating analysis was performed, and the results indicated that on MPWS the cardiac cells expressed significantly enhanced spontaneous synchronous beating. In contrast, the behavior of cardiac cells on PWS and TCP were less synchronized and showed weak contractions in terms of beat velocity compared to MPWS but showed a similar number of beats per minute to be studied further (Figure c).…”

“…47,48 With regard to the interaction of cardiac cells on the scaffolds, immunofluorescence staining studies of connexin43 and αsarcomeric actin showed alignment of the cellular cytoskeleton in the direction of the nanofiber yarns in both PWS and MPWS with increased expression observed in α-mangostin coated scaffolds due its cardioprotective properties reported to prevent degeneration of myocardial tissues by inhibition of oxidative stress. 49,50 Furthermore, the functionality of cells by beating analysis was performed, and the results indicated that on MPWS the cardiac cells expressed significantly enhanced spontaneous synchronous beating. In contrast, the behavior of cardiac cells on PWS and TCP were less synchronized and showed weak contractions in terms of beat velocity compared to MPWS but showed a similar number of beats per minute to be studied further (Figure 7c).…”