Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension

Kim‐Mitsuyama, Shokei; Izumi, Yasukatsu; Izumiya, Yasuhiro; Namba, Masashi; Yoshida, Kaoru; Wake, Ryotaro; Yoshiyama, Minoru; Itoh, Hiroshi

doi:10.1038/sj.gt.3302670

Cited by 20 publications

(22 citation statements)

References 21 publications

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“…35 Thus, MCP-1 plays an important role in the process of cardiac hypertrophy and fibrosis. In this study, LV MCP-1 expression was significantly increased by Ang II in accordance with our previous report, 36 and the increase tended to be smaller in the LV of pirfenidone-treated mice. It was not obvious whether pirfenidone could inhibit cardiac MCP-1 expression in this study.…”

Section: Role Of Pirfenidone In Cardiac Hypertrophy T Yamazaki Et Alsupporting

confidence: 81%

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: Role Of Pirfenidone In Cardiac Hypertrophy T Yamazaki Et Alsupporting

confidence: 81%

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

et al. 2011

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“…Indeed, the overexpression of the naturally occurring dominant negative AP-1 monomer JunD attenuates phenylephrine (PE)-mediated myocyte hypertrophy (8) and the JunD-deficient mouse accentuates the pathological effects of aortic banding (9), suggesting that preferential JunD expression confers a "protective" effect. In contrast, c-Jun appears to be essential for many of the pathological features of endothelin-1 and PE stimulation (12,20), indicating that c-Jun may favor the "pathological" phenotype. Specifically, c-Jun Ϫ/Ϫ and JunB Ϫ/Ϫ animals are embryolethal (11), whereas c-Fos Ϫ/Ϫ mice (18,33), although displaying developmental alterations, remain viable.…”

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confidence: 70%

AFos inhibits phenylephrine-mediated contractile dysfunction by altering phospholamban phosphorylation

Jeong

Walker

Brown

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Using neonatal rat ventricular myocytes, we previously reported that the expression of a dominant negative form of the c-Fos proto-oncogene (AFos) inhibited activator protein 1 activity and blocked the induction of the pathological gene profile stimulated by phenylephrine (PE) while leaving growth unaffected. We now extend these observations to the adult rat ventricular myocyte (ARVM) to understand the relationship between gene expression, growth, and function. Ventricular myocytes were isolated from adult rats and infected with adenovirus expressing beta-galactosidase (control) or AFos. The cells were subsequently treated with PE, and protein synthesis, gene program, calcium transients, and contractility were evaluated. As seen with the neonatal rat ventricular myocytes, in control cells PE stimulated an increase in protein synthesis, induced the pathological gene profile, and exhibited both depressed contractility and calcium transients. Although ARVMs expressing AFos still had PE-induced growth, pathological gene expression as well as contractility and calcium handling abnormalities were inhibited. To determine a possible mechanism of the preserved myocyte function in AFos-expressing cells, we examined phospholamban (PLB) and sarco(endo)plasmic reticulum calcium-ATPase proteins. Although there was no change in total PLB or sarco(endo)plasmic reticulum calcium-ATPase expression in response to PE treatment, PE decreased the phosphorylation of PLB at serine-16, an observation that was prevented in AFos-expressing cells. In conclusion, although PE-induced growth was unaffected in AFos-expressing ARVMs, the expression of the pathological gene profile was inhibited and both contractile function and calcium cycling were preserved. The inhibition of functional deterioration was, in part, due to the preservation of PLB phosphorylation.

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“…We recently demonstrated that c-Jun inhibition decreases MCP-1 gene expression in human tubular epithelial cells (de Borst et al, 2007a). Conversely, dominant-negative c-Jun gene therapy reduced myocardial MCP-1 expression in a model of cardiac hypertrophy (Kim-Mitsuyama et al, 2006). Furthermore, the 5Ј-flanking region of the MCP-1 gene contains multiple activator protein-1 sites (Nakayama et al, 2001), supporting the hypothesis that JNK regulates MCP-1 gene expression through the transcription factor c-Jun, which is an important part of the activator protein-1 complex.…”

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confidence: 99%

c-Jun NH₂-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

Borst

Prakash

Sandovici

et al. 2009

J Pharmacol Exp Ther

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Chronic inflammation is a major outcome determinant in several renal disorders. Induction of monocyte chemoattractant protein (MCP)-1 expression in tubular epithelial cells contributes importantly to the recruitment of inflammatory cells from the circulation toward the damaged tubulo-interstitium. Because the MCP-1 gene contains several c-Jun binding sites, we hypothesized that the c-Jun NH 2 -terminal kinase (JNK) pathway regulates MCP-1 expression and subsequently tubulointerstitial inflammation. This was investigated in cultured rat tubular epithelial cells (NRK-52E) and in the rat unilateral ischemia/reperfusion (I/R) model. In NRK-52E cells, the JNK inhibitor anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone (SP600125) reduced interleukin-1␤-, transforming growth factor-␤-, or bovine serum albumin-induced MCP-1

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Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension

Cited by 20 publications

References 21 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

AFos inhibits phenylephrine-mediated contractile dysfunction by altering phospholamban phosphorylation

c-Jun NH₂-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

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Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension

Cited by 20 publications

References 21 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

AFos inhibits phenylephrine-mediated contractile dysfunction by altering phospholamban phosphorylation

c-Jun NH2-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

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c-Jun NH₂-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation