Functional and structural impact of pirfenidone on the alterations of cardiac disease and diabetes mellitus

Ávila, Guillermo; Osornio-Garduño, Diana Stephanie; Ríos-Pérez, Erick Benjamín; Ramos-Mondragón, Roberto

doi:10.1016/j.ceca.2014.07.008

Cited by 12 publications

(9 citation statements)

References 90 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

mentioning

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

View full text Add to dashboard Cite

show abstract

“…With regards to pirfenidone and nintedanib (the approved anti-fibrotic drugs), there exists limited data in the literature on the cardioprotective effects of these agents in the bleomycin model. However, pirfenidone, has been shown to produce beneficial actions on the heart (Avila et al, 2014 ). It would be interesting to evaluate the cardiopulmonary effects of a combination therapy with C21 and pirfenidone/nintedanib.…”

Section: Discussionmentioning

confidence: 99%

The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury

et al. 2018

View full text Add to dashboard Cite

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT2 receptor by C21 attenuates bleomycin-induced lung injury and associated cardiopulmonary pathology, which needs to be further explored as a promising approach for the clinical treatment of IPF and Group III PH.

show abstract

“…Changes in expression levels of proteins controlling the development of fibrosis (e.g., TGF-β1), inflammation (e.g., interleukins) and oxidative stress (e.g., catalase) are involved. To date, however, the molecular targets responsible for these changes remain unknown (Avila et al, 2014; Lopez-de la Mora et al, 2015; Graziani et al, 2018). Free radicals are the only PFD-binding molecules identified thus far.…”

Section: Discussionmentioning

confidence: 99%

“…In marked contrast, little is known about the corresponding molecular mechanisms. A reduction in tissue fibrosis and stiffness, attributed to low expression levels of a profibrogenic cytokine (transforming growth factor-beta 1, or TGF-β1) is thought to be involved (Avila et al, 2014; Lopez-de la Mora et al, 2015; Graziani et al, 2018). Nevertheless, some effects do not require lowering levels of TGF-β1 or fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Regulation of Excitation–Contraction Coupling and Oxidative Stress in Cardiac Myocytes by Pirfenidone

2018

Self Cite

View full text Add to dashboard Cite

Pirfenidone (PFD) is used to treat human pulmonary fibrosis. Its administration to animals with distinct forms of cardiovascular disease results in striking improvement in cardiac performance. Here, its functional impact on cardiac myocytes was investigated. Cells were kept 1–2 days under either control culture conditions or the presence of PFD (1 mM). Subsequently, they were subjected to electrical stimulation to assess the levels of contractility and intracellular Ca2+. The PFD treatment promoted an increase in both peak contraction and kinetics of shortening and relaxation. Moreover, the amplitude and kinetics of Ca2+ transients were enhanced as well. Excitation–contraction coupling (ECC) was also investigated, under whole-cell patch-clamp conditions. In keeping with a previous report, PFD increased twofold the density of Ca2+ current (ICa). Notably, a similar increase in the magnitude of Ca2+ transients was also observed. Thus, the gain of ECC was unaltered. Likewise, PFD did not alter the peak amplitude of caffeine-induced Ca2+ release, indicating stimulation of Ca2+-induced–Ca2+-release (CICR) at constant sarcoplasmic reticulum Ca2+ load. A phase-plane analysis indicated that PFD promotes myofilament Ca2+ desensitization, which is being compensated by higher levels of Ca2+ to promote contraction. Interestingly, although the expression of the Na+/Ca2+ exchanger (NCX) was unaffected, the decay of Ca2+ signal in the presence of caffeine was 50% slower in PFD-treated cells (compared with controls), suggesting that PFD downregulates the activity of the exchanger. PFD also inhibited the production of reactive oxygen species, under both, basal conditions and the presence of oxidative insults (acetaldehyde and peroxide hydrogen). Conversely, the production of nitric oxide was either increased (in atrial myocytes) or remained unchanged (in ventricular myocytes). Protein levels of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) were also investigated. eNOS values did not exhibit significant changes. By contrast, a dual regulation was observed for nNOS, which consisted of inhibition and stimulation, in ventricular and atrial myocytes, respectively. In the latter cells, therefore, an up-regulation of nNOS was sufficient to stimulate the synthesis of NO. These findings improve our knowledge of molecular mechanisms of PFD action and may also help in explaining the corresponding cardioprotective effects.

show abstract

Functional and structural impact of pirfenidone on the alterations of cardiac disease and diabetes mellitus

Cited by 12 publications

References 90 publications

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

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

The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury

Long-Term Regulation of Excitation–Contraction Coupling and Oxidative Stress in Cardiac Myocytes by Pirfenidone

Contact Info

Product

Resources

About