Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

Hypertens Res. 2012 Nov;35(11):1063-8. doi: 10.1038/hr.2012.92. Epub 2012 Jul 5.

Abstract

Lysyl oxidase (LOX) and LOX-like protein-1 (LOXL-1) are extracellular matrix-embedded amine oxidases that have critical roles in the cross-linking of collagen and elastin. LOX family proteins are abundantly expressed in the remodeled heart of animals and humans and are implicated in cardiac fibrosis; however, their role in cardiac hypertrophy is unknown. In this study, in vitro stimulation with hypertrophic agonists significantly increased LOXL-1 expression, LOX enzyme activity and [(3)H] leucine incorporation in neonatal rat cardiomyocytes. A LOX inhibitor, beta-aminopropionitrile (BAPN), inhibited agonist-induced leucine incorporation in cardiomyocytes in vitro, suggesting the involvement of LOXL-1 in cardiomyocyte hypertrophy. Abdominal aortic constriction in rats produced left ventricular hypertrophy in parallel with LOXL-1 mRNA upregulation. And BAPN administration significantly inhibited angiotensin II-induced cardiac hypertrophy in vivo. These results suggest a role of LOXL-1 in cardiac hypertrophy in vivo. We generated transgenic mice with cardiomyocyte-specific expression of LOXL-1. LOXL-1 transgenic mice pups were born normally and grew to adulthood without increased mortality; these mice exhibited a greater left ventricle to body weight ratio, larger myocyte diameter, and more brain natriuretic peptide expression than their wild-type littermates. Echocardiography revealed that the LOXL-1 transgenic mice also had greater wall thickness with preserved cardiac contraction. Our results indicate a possible fundamental role of LOXL-1 in cardiac hypertrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / antagonists & inhibitors
  • Amino Acid Oxidoreductases / genetics*
  • Amino Acid Oxidoreductases / metabolism*
  • Aminopropionitrile / pharmacology
  • Angiotensin II / adverse effects
  • Angiotensin II / drug effects
  • Angiotensin II / pharmacology
  • Animals
  • Animals, Newborn
  • Cardiomegaly / chemically induced
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology*
  • Cells, Cultured
  • Disease Models, Animal
  • Echocardiography
  • Endothelin-1 / pharmacology
  • In Vitro Techniques
  • Leucine / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Rats
  • Rats, Wistar

Substances

  • Endothelin-1
  • Angiotensin II
  • Aminopropionitrile
  • Amino Acid Oxidoreductases
  • LOXL1 protein, rat
  • Loxl1 protein, mouse
  • Leucine