Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model

James T. Pearson, Misa Yoshimoto, Yi Ching Chen, Rohullah Sultani, Amanda J. Edgley, Hajime Nakaoka, Makoto Nishida, Keiji Umetani, Mark T. Waddingham, Hui Ling Jin, Yuan Zhang, Darren J. Kelly, Daryl O. Schwenke, Tadakatsu Inagaki, Hirotsugu Tsuchimochi, Issei Komuro, Shizuya Yamashita, Mikiyasu Shirai

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Abstract

Reduced clearance of lipoproteins by HDL scavenger receptor class B1 (SR-B1) plays an important role in occlusive coronary artery disease. However, it is not clear how much microvascular dysfunction contributes to ischemic cardiomyopathy. Our aim was to determine the distribution of vascular dysfunction in vivo in the coronary circulation of male mice after brief exposure to Paigen high fat diet, and whether this vasomotor dysfunction involved nitric oxide (NO) and or endothelium derived hyperpolarization factors (EDHF). We utilised mice with hypomorphic ApoE lipoprotein that lacked SR-B1 (SR-B1-/-/ApoER61h/h, n = 8) or were heterozygous for SR-B1 (SR-B1+/-/ApoER61h/h, n = 8) to investigate coronary dilator function with synchrotron microangiography. Partially occlusive stenoses were observed in vivo in SR-B1 deficient mice only. Increases in artery-arteriole calibre to acetylcholine and sodium nitroprusside stimulation were absent in SR-B1 deficient mice. Residual dilation to acetylcholine following L-NAME (50 mg/kg) and sodium meclofenamate (3 mg/kg) blockade was present in both mouse groups, except at occlusions, indicating that EDHF was not impaired. We show that SR-B1 deficiency caused impairment of NO-mediated dilation of conductance and microvessels. Our findings also suggest EDHF and prostanoids are important for global perfusion, but ultimately the loss of NO-mediated vasodilation contributes to atherothrombotic progression in ischemic cardiomyopathy.

Original languageEnglish
Article number18108
Number of pages13
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 22 Dec 2017

Keywords

  • cardiovascular diseases
  • experimental models of disease

Cite this

Pearson, J. T., Yoshimoto, M., Chen, Y. C., Sultani, R., Edgley, A. J., Nakaoka, H., Nishida, M., Umetani, K., Waddingham, M. T., Jin, H. L., Zhang, Y., Kelly, D. J., Schwenke, D. O., Inagaki, T., Tsuchimochi, H., Komuro, I., Yamashita, S., & Shirai, M. (2017). Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model. Scientific Reports, 7(1), [18108]. https://doi.org/10.1038/s41598-017-18485-6