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

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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.

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Acknowledgements

The authors wish to thank Cynthia Roberts, Qinge Lu, and Sutapa Santra for the technical assistance. This work was supported by National Institute of Neurological Disorders and Stroke R01 NS083078-01A1 (JC) and R01 NS099030-01 (JC).

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Authors and Affiliations

  1. Henry Ford Hospital Neurology, Detroit, MI, 48202, USA

    Jieli Chen, Chengcheng Cui, Poornima Venkat, Alex Zacharek, Peng Yu & Michael Chopp

  2. Gerontology Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Jieli Chen

  3. Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI, 48202, USA

    Xiaoping Yang & Jiang Xu

  4. Department of Physics, Oakland University, Rochester, MI, 48309, USA

    Michael Chopp

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  1. Jieli Chen
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Jieli Chen declares that she has no conflict of interest. Chengcheng Cui declares that she has no conflict of interest. Xiaoping Yang declares that she has no conflict of interest. Jiang Xu declares that he has no conflict of interest. Poornima Venkat declares that she has no conflict of interest. Alex Zacharek declares that he has no conflict of interest. Peng Yu declares that he has no conflict of interest. Michael Chopp declares that he has no conflict of interest.

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Chen, J., Cui, C., Yang, X. et al. MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke. Transl. Stroke Res. 8, 374–385 (2017). https://doi.org/10.1007/s12975-017-0520-z

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