Transgenic overexpression of the secreted, extracellular EGF-CUB domain-containing protein SCUBE3 induces cardiac hypertrophy in mice

doi:10.1016/j.cardiores.2007.03.014

Cardiovascular Research 2007 75(1):139-147; doi:10.1016/j.cardiores.2007.03.014

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Transgenic overexpression of the secreted, extracellular EGF-CUB domain-containing protein SCUBE3 induces cardiac hypertrophy in mice

Hsin-Yu Yang^a^,1, Ching-Feng Cheng^a^,b^,1, Bambang Djoko^a, Wei-Shiung Lian^a^,c, Cheng-Fen Tu^a, Ming-Tzu Tsai^a, Yen-Hui Chen^a, Chien-Chang Chen^a, Chien-Jui Cheng^d and Ruey-Bing Yang^a^,e^,*

^aInstitute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
^bDepartment of Pediatrics, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
^cDepartment of Animal Science and Technology, National Taiwan University, Taiwan
^dGraduate Institute of Medical Sciences and Department of Pathology, School of Medicine, Taipei Medical University, Taipei, Taiwan
^eInstitute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

^* Corresponding author. Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Sec. 2, Taipei 11529, Taiwan. Tel.: +886 2 2652 3943; fax: +886 2 2785 8847. rbyang{at}ibms.sinica.edu.tw

Objective The aim of this study was to investigate in a transgenicanimal model the cardiac expression and function of a novelextracellular protein SCUBE3 [signal peptide-CUB (complementproteins C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor)-likedomain-containing protein 3].

Methods and results Real-time quantitative reverse transcriptase(RT)-PCR analysis showed that SCUBE3 is expressed in the ventricularmyocardium. Male transgenic (TG) mice overexpressing SCUBE3appeared normal during development, from birth to adulthood.However, echocardiography and histopathological examinationrevealed significant cardiac hypertrophy in TG animals as theyaged, at 8 months. Interestingly, left-ventricle hypertrophyoccurred more rapidly and more severely under pressure overloadin TG mice, as compared to age-matched wild-type littermates.Induced SCUBE3 expression, together with elevated transforminggrowth factor (TGF)-β1 level under pressure overload, mayaccount for the accelerated onset and progression of cardiachypertrophy in TG mice. Furthermore, biochemical and molecularstudies revealed that the carboxyl-terminal portion of SCUBE3could physically interact with TGF-β1 and promote the TGF-β1-mediatedtranscriptional activation.

Conclusion This report is the first demonstration that SCUBE3may play a role in the regulation of cardiac growth and remodelingresponses, possibly through the stabilization of the TGF-β1signaling pathway.

KEYWORDS Transgenic animal models; Echocardiography; Hypertrophy; Myocytes; Extracellular matrix

¹ These authors contributed equally to this work.

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