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Treatment of long‐term coronary dysfunction in diabetes with mineralocorticoid receptor antagonism: vasomotor control and the MR‐dependent vascular transcriptome
Author(s) -
Brown Scott M,
Meuth Alex I,
Meers Grace M,
Davis J Wade,
Rector R Scott,
Bender Shawn B
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.836.22
Subject(s) - medicine , endocrinology , endothelial dysfunction , mineralocorticoid receptor , vasodilation , spironolactone , aldosterone , diabetes mellitus , mineralocorticoid , endothelium
Obesity and diabetes are associated with inappropriate activation of the renin‐angiotensin‐aldosterone system (RAAS) and impaired coronary microvascular function. We recently demonstrated that mineralocorticoid receptor (MR) antagonism with spironolactone (Spiro) treated coronary arteriolar endothelial dysfunction when administered during the development of dysfunction in obesity. Whether MR antagonism can treat long‐term established coronary arteriolar vasomotor dysfunction in diabetes and potential underlying molecular mechanisms have not been investigated. Here, we hypothesized that long‐term diabetes‐associated coronary arteriolar dysfunction will be abrogated by MR antagonism with Spiro involving alterations of the vascular transcriptome. Male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats (29 weeks of age) were treated with Spiro (sc, 20 mg/kg/d) or placebo for 3 weeks. Control, lean Long‐Evans Tokushima Otsuka (LETO) rats were treated with placebo and the onset of coronary microvascular dysfunction was established in separate groups of 5–8, 20, and 32 week old OLETF and LETO rats. At 32 weeks of age, OLETF rats exhibited obesity, hyperglycemia, hypercholesterolemia, normal blood pressure, and reduced circulating aldosterone compared to LETO. Endothelium‐dependent vasodilation of isolated, pressurized coronary arterioles to acetylcholine (ACh) was impaired at 5–8 weeks of age and persisted to 32 weeks in OLETF rats with no change in endothelium‐independent vasodilation to sodium nitroprusside. Further, coronary arteriolar vasoconstriction to endothelin‐1 (ET‐1) and the thromboxane mimetic U‐46619 increased significantly in an age‐dependent manner in OLETF rats. OLETF rats treated with Spiro exhibited similar plasma glucose, insulin, cholesterol, blood pressure, and serum potassium, but elevated circulating aldosterone compared to placebo‐treated OLETF rats at 32 weeks of age. Spiro treatment restored endothelium‐dependent coronary arteriolar vasodilation to ACh and insulin and attenuated coronary vasoconstriction to the L‐type calcium channel agonist BayK‐8644, but not to ET‐1 or U46619 in OLETF rats. RNA sequencing and Ingenuity Pathway Analysis of aortic mRNA from Spiro and placebo‐treated OLETF rats revealed MR‐dependent alterations of gene networks associated with iNOS, ceramide, and TNFR2 signaling. These data support and extend our recently published work by demonstrating that, independent of blood pressure, MR antagonism treats established diabetes‐associated coronary arteriolar endothelial dysfunction, an independent predictor of future cardiovascular events in human patients. In addition, these data highlight novel MR‐dependent alterations of the vascular transcriptome in diabetes that warrant further investigation. Support or Funding Information Supported by VHA BLR&D BX002030 (SBB) and VHA BLR&D BX001299 (RSR)