Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts

Yamagami, Kiyoshi; Oka, Tôru; Wang, Qi; Ishizu, Takamaru; Lee, Jong-Kook; Miwa, Keiko; Akazawa, Hiroshi; Naito, Atsuhiko T.; Sakata, Yasushi; Komuro, Issei

doi:10.1152/ajpheart.00137.2015

Cited by 86 publications

(65 citation statements)

References 35 publications

(32 reference statements)

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“…4) On the other hand, suppression of TGF-β can inhibit cardiac fibrosis in many experimental models. 26,27) TGF-β plays pivotal roles in collagen synthesis and cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

et al. 2017

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SummaryCardiac fibrosis is a pathological feature of myocardium of failing heart and plays causative roles in arrhythmia and cardiac dysfunction, but its regulatory mechanisms remain largely elusive. In this study, we investigated the effects of the novel EP4 receptor agonist ONO-0260164 on cardiac fibrosis in hypertrophied heart and explored the regulatory mechanisms in cardiac fibroblasts.In a mouse model of cardiac hypertrophy generated by transverse aortic constriction (TAC), ONO-0260164 treatment significantly prevented systolic dysfunction and progression of myocardial fibrosis at 5 weeks after TAC. In cultured neonatal rat cardiac fibroblasts, transforming growth factor-β1 (TGF-β1) induced upregulation of collagen type 1, alpha 1 (Col1a1) and type 3, alpha 1 (Col3a1), which was inhibited by ONO-0260164 treatment. ONO-0260164 activated protein kinase A (PKA) in the presence of TGF-β1 in the cardiac fibroblasts. PKA activation suppressed an increase in collagen expression induced by TGF-β1, indicating the important inhibitory roles of PKA activation in TGF-β1-mediated collagen induction.We have demonstrated for the first time the antifibrotic effects of the novel EP4 agonist ONO-0260164 in vivo and in vitro, and the important role of PKA activation in the effects. (Int Heart J 2017; 58: 107-114)

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“…4) On the other hand, suppression of TGF-β can inhibit cardiac fibrosis in many experimental models. 26,27) TGF-β plays pivotal roles in collagen synthesis and cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study revealed that serum albumin leakage and macrophage infiltration into the interstitial space were accelerated in pressure overload-induced heart failure. 4) This hyperpermeability state in the failing heart was expected to induce local and long lasting inflammation which contributes to cardiac fibrosis.…”

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confidence: 99%

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

et al. 2017

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“…Using the cardiac fibrosis mouse model at 4 weeks after surgical transverse aortic constriction (TAC)31, serpinE2 expression was increased obviously. Additionally, the protein and mRNA level of serpinE2 expression were also dramatically up-regulated in vitro induced by AngII or TGF-β stimulation.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

Zhao

Guo

et al. 2016

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Although increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis, the molecular mechanisms of pressure overload or AngII -induced cardiac interstitial fibrosis remain elusive. In this study, serpinE2/protease nexin-1 was over-expressed in a cardiac fibrosis model induced by pressure-overloaded via transverse aortic constriction (TAC) in mouse. Knockdown of serpinE2 attenuates cardiac fibrosis in a mouse model of TAC. At meantime, the results showed that serpinE2 significantly were increased with collagen accumulations induced by AngII or TGF-β stimulation in vitro. Intriguingly, extracellular collagen in myocardial fibroblast was reduced by knockdown of serpinE2 compared with the control in vitro. In stark contrast, the addition of exogenous PN-1 up-regulated the content of collagen in myocardial fibroblast. The MEK1/2- ERK1/2 signaling probably promoted the expression of serpinE2 via transcription factors Elk1 in myocardial fibroblast. In conclusion, stress-induced the ERK1/2 signaling pathway activation up-regulated serpinE2 expression, consequently led accumulation of collagen protein, and contributed to cardiac fibrosis.

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“…PFD is a novel anti-fibrotic agent that has shown promising results in various models and clinical trials1314. Cumulative evidence indicates the anti-fibrotic potential of PFD via inhibition of ACE and phospho-p38 MAPK in renal fibrosis and lung fibrosis, respectively1516.…”

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confidence: 99%

Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

Han

Kang

et al. 2017

Sci Rep

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Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and ±dp/dtmax changes induced by MI, which were associated with a reduction in cardiac fibrosis, infarct size, and hydroxyproline concentration. Moreover, PFD inhibited the AT1R/p38 MAPK pathway, corrected the RAS imbalance [decreased angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, but increased ACE2 and angiotensin (1-7) activity and Mas expression] and strongly enhanced heart LXR-α expression. These results indicate that the cardioprotective effects of PFD may be due, in large part, to controlling the feedback loop of the AT1R/p38 MAPK/RAS axis by activation of LXR-α.

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Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts

Cited by 86 publications

References 35 publications

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

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