Mice with tissue inhibitor of metalloproteinases 4 (Timp4) deletion succumb to induced myocardial infarction but not to cardiac pressure overload.
Tissue inhibitor of metalloproteinases 4 (TIMP4) is expressed highly in heart and found dysregulated in human cardiovascular diseases. It controls extracellular matrix remodeling by inhibiting matrix metalloproteinases (MMPs) and is implicated in processes including cell proliferation, apoptosis, and angiogenesis. Timp4-deficient mice (Timp4(-/-)) were generated to assess TIMP4 function in normal development and in models of heart disease. We deleted exons 1-3 of the Timp4 gene by homologous recombination. Timp4(-/-) mice are born healthy, develop normally, and produce litters of normal size and gender distribution. These mice show no compensation by overexpression of Timp1, Timp2, or Timp3 in the heart. Following cardiac pressure overload by aortic banding, Timp4(-/-) mice have comparable survival rate, cardiac histology, and cardiac function to controls. In this case, Timp4 deficiency is compensated by increased cardiac Timp2 expression. Strikingly, the induction of myocardial infarction (MI) leads to significantly increased mortality in Timp4(-/-) mice primarily due to left ventricular rupture. The post-MI mortality of Timp4(-/-) mice is reduced by administration of a synthetic MMP inhibitor. Furthermore, combining the genetic deletion of Mmp2 also rescues the higher post-MI mortality of Timp4(-/-) mice. Finally, Timp4(-/-) mice suffer reduced cardiac function at 20 months of age. Timp4 is not essential for murine development, although its loss moderately compromises cardiac function with aging. Timp4(-/-) mice are more susceptible to MI but not to pressure overload, and TIMP4 functions in its capacity as a metalloproteinase inhibitor after myocardial infarction.
Koskivirta
Ilpo
I
Department of Medical Biochemistry and Genetics, University of Turku, FI-20520 Turku, Finland.
Kassiri
Zamaneh
Z
Rahkonen
Otto
O
Kiviranta
Riku
R
Oudit
Gavin Y
GY
McKee
Trevor D
TD
Kytö
Ville
V
Saraste
Antti
A
Jokinen
Eero
E
Liu
Peter P
PP
Vuorio
Eero
E
Khokha
Rama
R
D000818:Animals; D001794:Blood Pressure; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000502:physiology; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics*; D011995:Recombination, Genetic; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000502:physiology*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4