Abstract
Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP. To investigate the genes responsible for the circadian variation in BP in hypertension, hypothalamic tissue was collected from BPH/2J and normotensive BPN/3J mice at the ‘peak’ (n = 12) and ‘trough’ (n = 6) of diurnal BP. Using Affymetrix GeneChip® Mouse Gene 1.0 ST Arrays, validation by quantitative real-time PCR and a statistical method that adjusted for clock genes, we identified 212 hypothalamic genes whose expression differed between ‘peak’ and ‘trough’ BP in the hypertensive strain. These included genes with known roles in BP regulation, such as vasopressin, oxytocin and thyrotropin releasing hormone, as well as genes not recognized previously as regulators of BP, including chemokine (C-C motif) ligand 19, hypocretin and zinc finger and BTB domain containing 16. Gene ontology analysis showed an enrichment of terms for inflammatory response, mitochondrial proton-transporting ATP synthase complex, structural constituent of ribosome, amongst others. In conclusion, we have identified genes whose expression differs between the peak and trough of 24-hour circadian BP in BPH/2J mice, pointing to mechanisms responsible for diurnal variation in BP. The findings may assist in the elucidation of the mechanism for the morning surge in BP in essential hypertension.
Highlights
Essential hypertension is a common [1] multifactorial condition involving the influence of numerous, mostly unidentified genes, generally thought to have small effects on blood pressure (BP) [2]
At ‘peak’ BP, Gene Ontology (GO) analysis showed an enrichment of terms such as neuropeptide signaling pathway, defense response, chemokine and cytokine activity, immune system development, mitochondrial protontransporting ATP synthase complex, and many terms related to structural constituent of ribosome, among others
The main findings suggest an involvement of arginine vasopressin (Avp), Oxt and thyrotropin releasing hormone (Trh), which are known genes in the regulation of BP
Summary
Essential hypertension is a common [1] multifactorial condition involving the influence of numerous, mostly unidentified genes, generally thought to have small effects on blood pressure (BP) [2]. Essential hypertensive patients display an exaggerated increase in BP levels in the morning, referred to as the morning BP surge [3] The basis of this phenomenon is not well understood. The identification of the mechanisms responsible for circadian variations in BP, in hypertensive patients, should assist in the design of new strategies for resolving the pathophysiology of this condition. In both animal models and humans, there is increasing evidence that the sympathetic nervous system (SNS) is involved in the development and progression of hypertension [5]. It was reported that acute sympathetic blockade decreases BP in the Schlager BPH/2J hypertensive mouse strain [8], consistent with involvement of the SNS in this genetic model of hypertension
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