Simvastatin reduces TGF-β1-induced SMAD2/3-dependent human ventricular fibroblasts differentiation: Role of protein phosphatase activation

Rizvi, Farhan; Siddiqui, Ramail; DeFranco, Alessandra; Homar, Peter; Emelyanova, Larisa; Holmuhamedov, Ekhson; Ross, Gracious R.; Tajik, A. Jamil; Jahangir, Arshad

doi:10.1016/j.ijcard.2018.06.061

Cited by 19 publications

(21 citation statements)

References 46 publications

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“…Myofibroblasts are defined by excessive α-SMA expression and EcM protein secretion (5,25). The present study demonstrated that TGF-β1 significantly promoted fibroblast differentiation and ECM protein expression, which is in accordance with the findings reported by previous studies (30,31,35). However, pre-incubation with ATV inhibited the TGF-β1-stimulated fibrotic response in hVFs.…”

Section: Discussionsupporting

confidence: 92%

“…Abnormal proliferation of CFs is the major cellular pathological basis of cardiac fibrosis. Increasing evidence suggests that TGF-β1, a key pro-fibrotic cytokine, can promote cF proliferation (30,31), which was confirmed in the present study. Furthermore, TGF-β1 has been demonstrated to be markedly and consistently activated in various cardiovascular diseases, including myocardial hypertrophy and myocardial infarction (32,33).…”

Section: Discussionsupporting

confidence: 88%

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Atorvastatin attenuates TGF‑β1‑induced fibrogenesis by inhibiting Smad3 and MAPK signaling in human ventricular fibroblasts

Xiao

Wan

et al. 2020

Int J Mol Med

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Excessive proliferation and myofibroblasts transformation of cardiac fibroblasts play a critical role in the process of cardiac fibrosis. Atorvastatin (ATV), a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, is commonly used to treat hypercholesterolemia. It has previously been shown that ATV has potential anti-fibrotic effects. However, the underlying mechanisms of ATV against cardiac fibrosis remain to be fully elucidated, and to the best of our knowledge, there are no reports focusing on the effects of ATV on transforming growth factor-β1 (TGF-β1)-induced human ventricular fibroblasts (hVFs) activation. In the present study, hVFs were stimulated with TGF-β1 with or without pretreatment with ATV. Subsequently, hVF proliferation, cytotoxicity, myofibroblast differentiation and pro-fibrotic gene expression were assessed. canonical and non-canonical signaling downstream of TGF-β1, such as Smad3 and mitogen-activated protein kinase (MAPK) signaling, were investigated by evaluating the phosphorylation levels of Smad3, extracellular signal-regulated kinase 1/2, p38 MAPK and c-Jun N-terminal kinase. The results indicated that ATV significantly prevented TGF-β1-induced cell proliferation, myofibroblast differentiation and production of extracellular matrix proteins, such as matrix metalloproteinase-2, collagen I and collagen III, in hVFs. Furthermore, ATV effectively inhibited TGF-β1-induced activation of Smad3 and MAPK signaling in hVFs. In conclusion, the present results demonstrated that ATV prevented TGF-β1-induced fibrogenesis in hVFs, at least in part by inhibiting the Smad3 and MAPK signaling pathways. Therefore, these results imply that ATV may be a promising agent to treat myocardial fibrosis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Atorvastatin attenuates TGF‑β1‑induced fibrogenesis by inhibiting Smad3 and MAPK signaling in human ventricular fibroblasts

Xiao

Wan

et al. 2020

Int J Mol Med

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“…HCF activation and differentiation into myofibroblasts promote cardiac fibrosis progression; however, the underlying mechanisms of CM-fibroblast communication in cardiac fibrosis and myofibroblast phenotypic expression that are regulated by exosomes remain unclear. Several studies demonstrated that SIM had an anti-fibrosis effect, such as reducing TGF-β1-induced SMAD2/3-dependent pathway activation and promoted human ventricular fibroblasts differentiation [45]. It also alleviated cardiac fibrosis-induced infarction by up-regulating TGF-β receptor III expression [25].…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Attenuates Cardiac Fibrosis via Regulation of Cardiomyocyte-Derived Exosome Secretion

Kuo

Hsieh

Wang

et al. 2019

JCM

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Exosome-mediated communication within the cardiac microenvironment is associated with cardiac fibrosis. Simvastatin (SIM), a potent statin, protects against cardiac fibrosis, but its mechanism of action is unclear. We investigated the inhibitory effects and underlying mechanism of simvastatin in cardiac fibrosis, by regulating exosome-mediated communication. Male Sprague-Dawley rats were treated with angiotensin (Ang) II alone, or with SIM for 28 d. Cardiac fibrosis, expressions of fibrosis-associated proteins and mRNAs, and collagen fiber arrangement and deposition were examined. Protein expressions in exosomes isolated from Ang II-treated cardiomyocytes (CMs) were evaluated using nano-ultra-performance liquid chromatographic system, combined with tandem mass spectrometry. Transformation of fibroblasts to myofibroblasts was evaluated using scanning electron and confocal microscopy, and migration assays. Our results showed that SIM attenuated in vivo expression of collagen and collagen-associated protein, as well as collagen deposition, and cardiac fibrosis. The statin also upregulated decorin and downregulated periostin in CM-derived exosomes. Furthermore, it suppressed Ang II-induced transformation of fibroblast to myofibroblast, as well as fibroblast migration. Exosome-mediated cell-cell communication within the cardiac tissue critically regulated cardiac fibrosis. Specifically, SIM regulated the release of CM exosomes, and attenuated Ang II-induced cardiac fibrosis, highlighting its potential as a novel therapy for cardiac fibrosis.

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“…Rosuvastatin, being hydrophilic, requires active transportation via organic anion transporting polypeptide 1B1 while lipophilic statins can passively diffuse into the cells . Although several prior in vitro studies have demonstrated statin‐induced prevention of differentiation to myofibroblasts, their ability to de‐differentiate already‐differentiated myofibroblasts is hitherto largely unknown. In addition to α‐SMA, the reduced expression of the negative regulator of fibrosis, Sprouty1, was reversed by simvastatin (Supporting Information, Figure ).…”

Section: Discussionmentioning

confidence: 99%

“…Statins are inhibitors of 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A (HMG‐CoA) reductase commonly prescribed for their lipid‐lowering effects in patients at risk of HF. Several prior in vitro studies have demonstrated statin‐induced prevention of differentiation to myofibroblasts, but their ability to de‐differentiate already‐differentiated myofibroblasts is unclear. Further, the impact of statins on human ventricular fibroblasts (hVFs) in HF patients is also not known.…”

Section: Introductionmentioning

confidence: 99%

Impact of statins on cellular respiration and de‐differentiation of myofibroblasts in human failing hearts

et al. 2019

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AimsFibroblast to myofibroblast trans‐differentiation with altered bioenergetics precedes cardiac fibrosis (CF). Either prevention of differentiation or promotion of de‐differentiation could mitigate CF‐related pathologies. We determined whether 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A (HMG‐CoA) reductase inhibitors—statins, commonly prescribed to patients at risk of heart failure (HF)—can de‐differentiate myofibroblasts, alter cellular bioenergetics, and impact the human ventricular fibroblasts (hVFs) in HF patients.Methods and resultsEither in vitro statin treatment of differentiated myofibroblasts (n = 3–6) or hVFs, isolated from human HF patients under statin therapy (HF + statin) vs. without statins (HF) were randomly used (n = 4–12). In vitro, hVFs were differentiated by transforming growth factor‐β1 (TGF‐β1) for 72 h (TGF‐72 h). Differentiation status and cellular oxygen consumption rate (OCR) were determined by α‐smooth muscle actin (α‐SMA) expression and Seahorse assay, respectively. Data are mean ± SEM except Seahorse (mean ± SD); P < 0.05, considered significant. In vitro, statins concentration‐dependently de‐differentiated the myofibroblasts. The respective half‐maximal effective concentrations were 729 ± 13 nmol/L (atorvastatin), 3.6 ± 1 μmol/L (rosuvastatin), and 185 ± 13 nmol/L (simvastatin). Mevalonic acid (300 μmol/L), the reduced product of HMG‐CoA, prevented the statin‐induced de‐differentiation (α‐SMA expression: 31.4 ± 10% vs. 58.6 ± 12%). Geranylgeranyl pyrophosphate (GGPP, 20 μmol/L), a cholesterol synthesis‐independent HMG‐CoA reductase pathway intermediate, completely prevented the statin‐induced de‐differentiation (α‐SMA/GAPDH ratios: 0.89 ± 0.05 [TGF‐72 h + 72 h], 0.63 ± 0.02 [TGF‐72 h + simvastatin], and 1.2 ± 0.08 [TGF‐72 h + simvastatin + GGPP]). Cellular metabolism involvement was observed when co‐incubation of simvastatin (200 nmol/L) with glibenclamide (10 μmol/L), a KATP channel inhibitor, attenuated the simvastatin‐induced de‐differentiation (0.84 ± 0.05). Direct inhibition of mitochondrial respiration by oligomycin (1 ng/mL) also produced a de‐differentiation effect (0.33 ± 0.02). OCR (pmol O2/min/μg protein) was significantly decreased in the simvastatin‐treated hVFs, including basal (P = 0.002), ATP‐linked (P = 0.01), proton leak‐linked (P = 0.01), and maximal (P < 0.001). The OCR inhibition was prevented by GGPP (basal OCR [P = 0.02], spare capacity OCR [P = 0.008], and maximal OCR [P = 0.003]). Congruently, hVFs from HF showed an increased population of myofibroblasts while HF + statin group showed significantly reduced cellular respiration (basal OCR [P = 0.021], ATP‐linked OCR [P = 0.047], maximal OCR [P = 0.02], and spare capacity OCR [P = 0.025]) and myofibroblast differentiation (α‐SMA/GAPDH: 1 ± 0.19 vs. 0.23 ± 0.06, P = 0.01).ConclusionsThis study demonstrates the de‐differentiating effect of statins, the underlying GGPP sensitivity, reduced OCR with potential activation of KATP channels, and their impact on the differentiation magnitude of hVFs in HF patients. ...

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Simvastatin reduces TGF-β1-induced SMAD2/3-dependent human ventricular fibroblasts differentiation: Role of protein phosphatase activation

Cited by 19 publications

References 46 publications

Atorvastatin attenuates TGF‑β1‑induced fibrogenesis by inhibiting Smad3 and MAPK signaling in human ventricular fibroblasts

Atorvastatin attenuates TGF‑β1‑induced fibrogenesis by inhibiting Smad3 and MAPK signaling in human ventricular fibroblasts

Simvastatin Attenuates Cardiac Fibrosis via Regulation of Cardiomyocyte-Derived Exosome Secretion

Impact of statins on cellular respiration and de‐differentiation of myofibroblasts in human failing hearts

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