A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy

Fadia Kamal, Kenichi Watanabe, Meilei Ma, Yuichi Abe, Reyad Elbarbary, Makoto Kodama, Yoshifusa Aizawa

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Regardless of the origin, injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis often progresses to dilated cardiomyopathy (DCM), a major cause of heart failure. In our study, we used a rat model of myosin-induced experimental autoimmune myocarditis (EAM), in which the heart transits from an acute phase (inflammatory myocarditis) to a chronic phase (remodeling and DCM). Our objective was to investigate whether T-3999, a novel phenylpyridazinone, can reduce this progression. Four weeks after myosin injection, T-3999 was administered daily to male Lewis rats in two doses (3 and 10 mg/kg, orally). Four weeks later, treatment was terminated; hemodynamic and echocardiographic measurements were performed; hearts were excised for histopathology and estimation of histamine, mRNA, and protein levels. Mortality rate was reduced by drug treatment. T-3999 reduced % fibrosis and tissue collagen III. Profibrotic markers-transforming growth factor-β1, tumor necrosis factor-α, and galectin-3-were attenuated by treatment. Mast cell density and degranulation, and tissue histamine concentration were also reduced. This indicates an anti-inflammatory effect of the drug in reducing fibrosis. Hypertrophy was reduced as reflected by reduced myocyte diameter and natriuretic peptide expression. T-3999 treatment increased the sarcoendoplasmic reticulum Ca2+ ATPase 2 protein level and improved several cardiac function parameters. The reduction of the remodeling process and improvement in myocardial function suggest an effect of T-3999 in attenuating ventricular remodeling in post-myocarditis DCM.

Original languageEnglish (US)
Pages (from-to)81-90
Number of pages10
JournalHeart and Vessels
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2011

Fingerprint

Myocarditis
Dilated Cardiomyopathy
Fibrosis
Myosins
Hypertrophy
Histamine
Heart Injuries
Galectin 3
Cell Degranulation
Reticulum
Natriuretic Peptides
Ventricular Remodeling
Calcium-Transporting ATPases
Transforming Growth Factors
Therapeutics
Cardiac Myocytes
Mast Cells
Pharmaceutical Preparations
Muscle Cells
Proteins

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Kamal, Fadia ; Watanabe, Kenichi ; Ma, Meilei ; Abe, Yuichi ; Elbarbary, Reyad ; Kodama, Makoto ; Aizawa, Yoshifusa. / A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy. In: Heart and Vessels. 2011 ; Vol. 26, No. 1. pp. 81-90.
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A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy. / Kamal, Fadia; Watanabe, Kenichi; Ma, Meilei; Abe, Yuichi; Elbarbary, Reyad; Kodama, Makoto; Aizawa, Yoshifusa.

In: Heart and Vessels, Vol. 26, No. 1, 01.01.2011, p. 81-90.

Research output: Contribution to journalArticle

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