The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy

J Clin Invest. 2002 Jul;110(2):271-9. doi: 10.1172/JCI14938.

Abstract

Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Atrial Natriuretic Factor / genetics
  • Blood Pressure / physiology*
  • Enzyme Activation
  • Gene Expression
  • Hypertrophy, Left Ventricular / etiology*
  • Hypertrophy, Left Ventricular / pathology
  • Hypertrophy, Left Ventricular / physiopathology
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / physiology*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Transforming Growth Factor beta / genetics
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Atrial Natriuretic Factor
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • Map3k1 protein, mouse