Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA‐salt hypertensive rats

Mirkovic, Stevo; Seymour, Anne-Marie L.; Fenning, Andrew; Strachan, Anna J.; Margolin, Solomon B.; Taylor, Stephen M.; Brown, Lindsay

doi:10.1038/sj.bjp.0704539

Cited by 118 publications

(99 citation statements)

References 31 publications

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“…In their study, pirfenidone treatment resulted in a significant reduction of atrial fibrosis. Mirkovic et al 11 reported that pirfenidone reverses and prevents cardiac remodeling as well as increased cardiac stiffness in deoxycorticosterone acetate-salt hypertensive rats. Those results suggest a broad effect of pirfenidone on potent profibrotic mediators.…”

Section: Discussionmentioning

confidence: 99%

“…The Ang II/AT1 receptor interaction generates an immediate calcium-dependent response and late nuclear factor-kB activation through the activation of different pathways, including protein kinase C, mitogen-activated protein kinase cascades, receptor tyrosine kinases and non-receptor tyrosine kinases. 2,4 Pirfenidone (5-methyl-1-phenyl-2-[ 1 H]-pyridone) has been shown to reduce the fibrosis of different organs (for example, lung 5,6 kidney 7-9 liver, 10 heart [11][12][13] ) and vascular remodeling 14 through its inhibitory effect on fibroblast growth and collagen synthesis, which is achieved by reducing the expression of profibrotic cytokines (for example, TGF-b 15,16 ). Furthermore, pirfenidone has been successfully used in a double-blind, placebo-controlled trial focused on patients with idiopathic pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice

et al. 2011

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Pirfenidone (5-methyl-1-phenyl-2-[ 1 H]-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg À1 min À1 ) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg À1 per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-b1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice

et al. 2011

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“…Pirfenidone is a recently developed broad spectrum antifibrotic agent with efficacy in preventing and resolving several kinds of fibrotic disease, including lung (11) and renal fibrosis (13), liver cirrhosis (15), cardiac remodeling, and increased cardiac stiffness (36). Several recent studies have been published about the efficacy of pirfenidone on idiopathic pulmonary fibrosis (IPF).…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Hirano

Kanehiro

Ono

et al. 2006

Am J Respir Cell Mol Biol

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We investigated the therapeutic potential of a newly developed antifibrotic agent, pirfenidone, to regulate airway remodeling and the development of allergic airway inflammation and airway hyperresponsiveness after chronic allergen challenge. Administration of pirfenidone after sensitization but during the period of ovalbumin challenge significantly prevented the development of airway hyperresponsiveness and prevented eosinophil and lymphocyte accumulation in the airways. IL-4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid and ovalbumin-specific serum IgE antibody levels were also significantly reduced. Treatment with pirfenidone significantly reduced transforming growth factor-␤1 and platelet-derived growth factor levels in bronchoalveolar lavage fluid. Pirfenidone reduced the expression of transforming growth factor-␤1, the development of goblet cell hyperplasia and subepithelial collagenization, and the increases in contractile elements in the lung. These data indicate that pirfenidone may play an important role in the treatment of asthma and has the potential reduce or prevent airway remodeling.

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“…Although some drugs interfering with TGF-␤ expression (i.e., pirfenidone and tranilast) have shown promising antifibrotic effects in animal models of hypertension (30,44), no evidence has been provided yet that this is due to the reduced expression of LOX. In contrast, the chronic in vivo blockade of the TGF-␤ type III receptor ␤-glycan with the peptide P144 has been shown to be associated with the reduced expression of LOX mRNA and the precursor and active form of LOX protein, as well as with the decrease in collagen cross-linking and deposition in the myocardium of treated SHRs (24).…”

Section: Therapeutic Modulation Of Lox In Cardiac Diseasesmentioning

confidence: 99%

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

López

González

Hermida

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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198

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Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOXmediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function. collagen; diastolic dysfunction; hypertensive heart disease; myocardial remodeling THE ELEVATION IN myocardial stress that results from cardiac injury and/or persistent elevations in ventricular pressure or volume triggers a response of the myocardium in an attempt to return the tissue stress to its normal value. This response leads to progressive structural remodeling of the cardiomyocyte, vascular and extracellular matrix (ECM) components of the myocardium that manifest as changes in ventricular wall and chamber dimensions, as well as in diastolic and systolic function (5).Alterations in the myocardial collagen network are a hallmark of the ECM response to stress, either hemodynamic or nonhemodynamic in origin. A collagen network, composed largely of collagen types I and III fibers, is found in the interstitial space of the myocardium. Because collagen is a relatively stiff material with a high-tensile strength, small changes in its concentration have been shown to exert marked effects on the passive mechanical properties of the human heart (7). In addition to the concentration of collagen, experimental data suggest that the passive behavior of the myocardium may also be dependent on the relative proportion of the types of collagen, the diameter of the collagen fibers and their spatial alignment, and the degree of cross-linking. Accordingly, tissue containing predominantly type I collagen, large-diameter collagen fibers, and/or a high degree of cross-lin...

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Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA‐salt hypertensive rats

Cited by 118 publications

References 31 publications

The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice

The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice

Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

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