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S248

Journal of Cardiac Failure Vol. 11 No. 9 Suppl. 2005

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Identification of a Molecular Therapeutic Target for Abdominal Aortic Aneurysm HIROKI AOKI1, KOICHI YOSHIMURA1, YASUHIRO IKEDA1, KOZO FUJII1, NORIO AKIYAMA2, AKIRA FURUTANI2, YOSHINOBU HOSHII3, NOBUYUKI TANAKA4, ROMEO RICCI5, TOKUHIRO HAMANO2, ISHIHARA3, KENSUKE ESATO2, KIMIKAZU MASUNORI MATSUZAKI1 1 Department of Molecular Cardiovascular Biology, 2First Department of Surgery, 3First Department of Pathology, 4Department of Radiology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan, 5ETH Ho¨nggerberg, Institute of Cell Biology, Zurich, Switzerland

Overexpression of Mitochondrial Transcription Factor A Ameliorates Mitochondrial Deficiencies and Cardiac Failure HIROYUKI TSUTSUI Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Although we have gained much knowledge about the signal transduction pathways at the molecular level in physiological and pathophysiological conditions in the last decades, it is still a major challenge to identify a molecular therapeutic target in a given disease. We describe a signaling pathway-oriented global transcriptional analysis, which identified JNK, a stress-activated protein kinase, as a proximal signaling molecule in the pathogenesis of abdominal aortic aneurysm (AAA). AAA is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. AAA has long been considered an irreversible destructive process and regression of AAA by non-surgical methods has not been expected. We show that JNK programs a gene expression pattern that cooperatively enhances the degradation of the extracellular matrix, while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in mice. These results revealed that JNK promotes abnormal ECM metabolism in AAA and represents a novel “druggable” therapeutic target for AAA.

Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state. We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in the post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type littermates (WT)MI although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT-MI and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV. Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure.

S2-1 Keynote Lecture

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Role of Inflammation in Heart Failure: New Insights into Pathogenesis and Treatment AKIRA MATSUMORI Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

PETER P. LIU The Toronto General Hospital University Health Network, Toronto, Canada

Recently, inflammation has been shown to be an important aspect of heart failure (HF), and markers of inflammation predict risk of adverse events. Infection, immunity and inflammation are closely involved in the development of heart failure. The roles of hepatitis C virus infection, cytokines, NF- kB, angiotensin II (AII), and mast cells in the pathogenesis of HF will be discussed. We have shown that mast cells play an important role in the pathogenesis of heart failure, and that mast cells have preformed AII in their granules, and release AII by stimulation by neuropeptide. Furthermore, AII activates NF-kB, and induces inflammation. Thus, mast cells /AII/ NF-kB pathway will be a therapeutic target of HF. Human immunoglobulin light-chain kappa and lambda, are present as free light chains (FLCs) in serum, and have been shown to mediate antigenspecific, mast cell-dependent hypersensitivity-like responses. Our recent study showed that concentrations of circulating FLC kappa and lambda were significantly higher, and the FLC kappa/lambda ratio was lower in HF patients than in controls. This study suggests that polyclonal B lymphocytes are activated, and that the production of FLCs is increased in HF. These observations introduce a new concept in which inflammation provides a functional link between immune activation and development of HF, and point to new investigations directed toward its pathogenesis and treatment.