Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction

Graziani, Francesca; Lillo, Rosa E.; Crea, Filippo

doi:10.3389/fcvm.2021.678530

Cited by 7 publications

(4 citation statements)

References 92 publications

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“…60 The new HFpEF paradigm states that coronary microvascular inflammation and myocardial fibrosis can be considered the central theme in the HFpEF conundrum, and antifibrotic drugs, such as PFD, may be effective tools in blocking this pathological mechanism. 61 The following section summarises evidence about PFD's antifibrotic activity in various animal models of cardiac disease, including pressure overload, diabetes and anthracycline-induced cardiomyopathies, MI, AF and Duchenne muscular dystrophy (DMD; Figure 1).…”

Section: Pirfenidone As a Possible Cardiac Protective Drugmentioning

confidence: 99%

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

et al. 2022

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Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug.

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Section: Pirfenidone As a Possible Cardiac Protective Drugmentioning

confidence: 99%

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

et al. 2022

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“…Pirfenidone is an antifibrotic drug that has been approved for treating patients with idiopathic pulmonary fibrosis (Shah et al, 2021). Its possible application in other diseases including heart failure with preserved ejection fraction (Graziani et al, 2021), nonalcoholic steatohepatitis (Komiya et al, 2017), and advanced liver fibrosis (Poo et al, 2020) has also been investigated. Pirfenidone functions against fibrosis by targeting the TGF-b signaling pathway .…”

Section: Discussionmentioning

confidence: 99%

Ligustrazine Attenuates Liver Fibrosis by Targeting miR-145 Mediated Transforming Growth Factor-β/Smad Signaling in an Animal Model of Biliary Atresia

Qiu

Chai

Han

et al. 2022

J Pharmacol Exp Ther

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To investigate therapeutic target for ligustrazine during liver fibrosis in an ethanol-induced biliary atresia rat model and transforming growth factor-b (TGF-b) induced hepatic stellate cell activation cell model, and the underlying mechanism, a total of 30 rats were randomly assigned into five groups (n 5 6 per group): control, sham, ethanol-induced biliary atresia model, model plus pirfenidone, and model plus ligustrazine groups. The liver changes were assessed using H&E and Masson staining and transmission electron microscopy. Expression of miR-145 and mRNA and protein levels of TGF-b/smads pathway-related proteins were detected. HSC-T6 cells were infected with LV-miR or rLV-miR-145 in the presence or absence of SMAD3 inhibitor SIS3 and treated with 2.5 ng/ml TGF-b1 and then with ligustrazine. Collected cells were subjected to detect the expression of miR-145 and mRNA and protein expression levels of TGF-b/smads pathwayrelated proteins. Ligustrazine rescued liver fibrogenesis and pathology for ethanol-caused bile duct injury, revealed by decreased a-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Further experiments showed that ligustrazine inhibited intrinsic and phosphorylated Smad2/3 protein expression and modification. Similar results were obtained in cells.In addition, ligustrazine altered miR-145 expression in both animal and cell models. Lentivirus mediated miR-145 overexpression and knockdown recombinant virus showed that miR-145 enhanced the TGF-b/Smad pathway, which led to hepatic stellate cell activation, and ligustrazine blocked this activation. This work validated that ligustrazine-regulated miR-145 mediated TGF-b/Smad signaling to inhibit the progression of liver fibrosis in a biliary atresia rat model and provided a new therapeutic strategy for liver fibrosis. SIGNIFICANCE STATEMENTWith an ethanol-induced biliary atresia rat model, ligustrazine was found to rescue liver fibrogenesis and pathology for ethanol caused bile duct injury, revealed by decreased a-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Furthermore, we found ligustrazine upregulated miR-145 expression and inhibited TGF-b/SMAD signaling pathway both in vivo and in vitro. In addition, overexpression and knockdown of miR-145 confirmed that miR-145 is involved in the ligustrazine inhibition of liver fibrosis through the TGF-b/SMAD signaling pathway.

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“…The mechanism of action of pirfenidone has been clarified only in part; nevertheless, a deeper understanding of its molecular features is an essential premise to a wider indication for diseases characterized by extensive fibrosis such as heart failure and hypertrophic cardiomyopathy ( 7 , 8 ). For this reason, it is essential to have a brief excursus on the mechanisms underpinning cardiac fibrosis.…”

Section: Pharmacological Propertiesmentioning

confidence: 99%

Pharmacological basis of the antifibrotic effects of pirfenidone: Mechanistic insights from cardiac in-vitro and in-vivo models

Sartiani

Bartolucci²,

Pallecchi³

et al. 2022

Front. Cardiovasc. Med.

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Pirfenidone is a small drug with marked antifibrotic activity approved for the treatment of Idiopathic pulmonary fibrosis. Recently, its peculiar pharmacological profile has attracted attention for its potential therapeutic benefit for extra-pulmonary disorders characterized by pathological fibrosis, such as kidney, liver, and cardiac failure. A major pitfall of pirfenidone is the lack of consistent understanding of its mechanism of action, regardless of the target. In addition to the increasing attention to the role of inflammation and its mediators in several processes, a better knowledge of the variety of fibroblasts' population, of signals controlling their activation and trans-differentiation, and of crosstalk with other cell resident and non-resident cell types is needed for prevention, treatment and possibly reverse of fibrosis. This review will focus on pirfenidone's pharmacological profile and its effects on cardiac fibroblasts.

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Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction

Cited by 7 publications

References 92 publications

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

Ligustrazine Attenuates Liver Fibrosis by Targeting miR-145 Mediated Transforming Growth Factor-β/Smad Signaling in an Animal Model of Biliary Atresia

Pharmacological basis of the antifibrotic effects of pirfenidone: Mechanistic insights from cardiac in-vitro and in-vivo models

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