Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage.

Autor:	Khan SI; Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia shanzana.khan@monash.edu.; Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.; Department of Medicine, Monash University, Melbourne, Victoria, Australia., Andrews KL; Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.; Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia., Jefferis AM; Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.; Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia., Jennings GL; Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.; Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia., Sampson AK; Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia., Chin-Dusting JPF; Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.; Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
Jazyk:	angličtina
Zdroj:	Clinical science (London, England : 1979) [Clin Sci (Lond)] 2018 Jan 16; Vol. 132 (1), pp. 131-143. Date of Electronic Publication: 2018 Jan 16 (Print Publication: 2018).
DOI:	10.1042/CS20171291
Abstrakt:	Vascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels. (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
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