Extracellular Matrix Remodeling in Cardiovascular Diseases
Target Investigator:
Takeshi Tsuda, MD
Physician – Cardiology
Collaborator: Robert Akins, Ph.D., Nemours Biomedical Research
Mentors: Thomas H. Shaffer, MS.E., Ph.D., Nemours Biomedical Research
Robert Sikes, Ph.D., University of Delaware
Jeffery Twiss, M.D., Ph.D., Nemours Biomedical Research


Heart failure is a major clinical and public health problem in the US with considerable morbidity and mortality. Approximately, 4.7 Million people are involved with 400,000 to 700,000 new cases/yr costing $15 to 40 Billion/Yr. As such, this problem is a major complication in patients with congenital heart disease and the mechanisms of heart failure are heterogeneous, complex, and poorly understood. Following myocardial injury and/or mechanical overload, the heart can initially maintain cardiac output by enhancing intrinsic compensatory capacity. However, a persistent mismatch between intrinsic compensatory capacity and increased workload will eventually induce further functional deterioration and alteration in ventricular geometry (ventricular remodeling). The current project addresses the factors and mechanisms which regulate the transition from benign compensatory hypertrophy to heart failure.

In order to study these mechanistic pathways, we propose to study In vivo mouse models [fibulin-2 knock out (F2KO) and wild type (WT)] to experimentally induce heart failure by: 1) Myocardial infarction and 2) Chronic pressure overload. In addition, In vitro cell culture models will be studied to address the underlying cellular mechanisms by utilizing: 1) Adult mouse cardiac fibroblasts (F2KO and WT) and 2) Neonatal rat ventricular cardiomyocytes. Thus, the project is directed at the regulation of cardiovascular function from compensation to failure.


Figure 1. Schematic of the pathway for myocardial injury and/or mechanical overload to heart failure. As shown, the schematic suggests Angiotensin II (Ang II)/ TGF- β1 interaction with cardiac fibroblasts and myocytes, leading to extracellular matrix (ECM) remodeling, myocyte hypertrophy and apoptosis. The end result of these interactions is heart failure.
Figure 2. Histological results of collagen type I (percent wall area) in wild type (WT) and fibulin -2 knock out (Fbin 2 KO) mice after induced heart failure.

Related Publications:

    Chu, M-L, Tsuda T. Fibulins in Development and Heritable Disease. Birth Defects Research (Part C) Embryo Today 72:25-36, 2004.
    Tsuda T, Chu M-L. “Biological role of fibulin-2 in cardiovascular development”, in Cardiovascular Development and Congenitial Malformation, Edited by Artman M, Benson DW, Srivastava D, Nakazawa M, Blackwell Futura, p 20-23, 2005.
    Miller TL, Altman AR, Tsuda T, Shaffer TH: An ultrasound imaging method for in vivo tracheal bulk and Young’s moduli of elasticity. J Biomech 40(7):1615-1621, 2007.
    Kobayashi N, Kostka G, Garbe JHO, Keene DR, Bächinger, Hanisch F-G, Markova D, Tsuda T, Timpl R, Chu M-L, Sasaki T. A comparative analysis of the fibulin protein family: Biochemical characterization, binding interactions and tissue localization. J Biol Chem 282; 11805-11816, 2007.
    Akins RE, Gratton K, Quezada E, Rutter H, Tsuda T, Soteropoulos P. Gene expression profile of bioreactor-cultured cardiac cells: Activation of morphogenetic pathways for tissue engineering. DNA Cell Biol 26; 425-434, 2007.
    Mizuno J, Akune T, Tsuda T, Fukui Y, Otsuji M, Kin N, Saito Y, Orii R, Hayashida M, Arita H, Hanaoka K. Time course of systolic and diastolic blood pressure decreases during the preintubation period of anesthesia induction: Modeling with a logistic function. J Clin Anesthesia 19:497-505, 2007.
    Sicot F-X*, Tsuda T*, Markova D, Klemment JF, Birk D, Chu M-L. Fibulin-2 is a dispensable for mouse development and elastic fiber formation. Mol Cell Biology 28; 1061-1067, 2008 (*equal contribution).
    Mizuno J, Tsuda T, Otsuji M, Arita H, Nanaoka K: Assessment by logistic model of hemodynamic changes during teneral anesthetic. Masui 57:341-351, 2008.