MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke

Transl Stroke Res. 2017 Aug;8(4):374-385. doi: 10.1007/s12975-017-0520-z. Epub 2017 Jan 19.

Abstract

Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA-126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR-126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126EC-/-), and miR-126 knockout control (miR-126fl/fl) mice were subjected to distal middle cerebral artery occlusion (dMCAo) (n = 10/group). Cardiac hemodynamics and function were measured using transthoracic Doppler echocardiography. Mice were sacrificed at 28 days after dMCAo. WT mice subjected to stroke exhibited significantly decreased cardiac ejection fraction and increased myocyte hypertrophy, fibrosis as well as increased heart inflammation, infiltrating macrophages, and oxidative stress compared to non-stroke animals. Stroke significantly decreased serum and heart miR-126 expression and increased miR-126 target genes, vascular cell adhesion protein-1, and monocyte chemotactic protein-1 gene, and protein expression in the heart compared to non-stroke mice. MiR-126EC-/- mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126fl/fl stroke mice. Exosomes derived from endothelial cells of miR-126EC-/- (miR-126EC-/-EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR-126fl/fl (miR-126fl/fl-EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126fl/fl-EC-Exo exhibited significantly decreased hypertrophy than with miR-126EC-/-EC-Exo treatment. Ischemic stroke directly induces cardiac dysfunction. Decreasing miR-126 expression may contribute to cardiac dysfunction after stroke in mice.

Keywords: Brain-heart interaction; Cardiac dysfunction; Cardiomyocyte; Ischemia; MicroRNA-126; Stroke.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Animals, Newborn
  • Brain / metabolism*
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Gene Expression Regulation / genetics
  • Heart Diseases / etiology*
  • Heart Diseases / metabolism
  • Heart Diseases / pathology
  • Infarction, Middle Cerebral Artery / complications*
  • Infarction, Middle Cerebral Artery / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NADPH Oxidase 2 / genetics
  • NADPH Oxidase 2 / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Actins
  • Chemokine CCL2
  • MIRN126 microRNA, mouse
  • MicroRNAs
  • Transforming Growth Factor beta
  • Vascular Cell Adhesion Molecule-1
  • NADPH Oxidase 2