Contribution of Autosomal Loci and the Y Chromosome to the Stress Response in Rats

Abstract

Abstract-Stress is a critical contributor to cardiovascular diseases through its impact on blood pressure variability and cardiac function. Familial clustering of reactivity to stress has been demonstrated in human subjects, and some rodent models of hypertension are hyperresponsive to stress. Therefore, the present study was designed to uncover the genetic determinants of the stress response. We performed a total genome linkage search to identify the loci of the body temperature response to immobilization stress in a set of recombinant inbred strains (RIS) originating from reciprocal crosses of spontaneously hypertensive rats (SHR) with a normotensive Brown Norway Lx strain. Two quantitative trait loci (QTLs) were revealed on chromosomes (Chrs) 10 and 12 (logarithm of odds scores, 2.2 and 1.3, respectively). The effects of these QTLs were enhanced by a high sodium diet (logarithm of odds scores, 4.0 and 3.3 for Chrs 10 and 12, respectively), which is suggestive of a salt-sensitive component for the phenotype. Congenics for Chr 10 confirmed both the QTL and the salt effect in RIS. Negatively associated loci were also identified on Chrs 8 and 11. Interaction between the loci of Chrs 10 and 12 was demonstrated, with the rat strains bearing SHR alleles at both loci having the highest thermal response to stress. Furthermore, the Y Chr of SHR origin enhanced the response to immobilization stress, as demonstrated in 2 independent models, RIS and Y Chr consomics. However, its full effect requires autosomes of the SHR strain. These findings provide the first evidence for the genetic determination of reactivity to stress with interactions between autosomal loci and between the Y and autosomal Chrs that contribute to the explanation of the 46% of variance in the stress response. T he response to environmental stress is a predictor of cardiovascular diseases, including future high blood pressure (BP), in prehypertensive patients with a positive family history 1 and the development of left ventricular hypertrophy. 2 Spontaneously hypertensive rats (SHR) and mice are more reactive to stress than their normotensive counterparts. 3-6 On exposure to several psychogenic stressors, such as cage-switch, placement in an open field, or immobilization, they display higher changes in heart rate, BP, and body temperature (BT). 5,7 The increase in BT with immobilization stress may, thus, be proposed as an intermediate phenotype of the stress response. To identify the genetic determinants of the BT response to immobilization stress, we performed a full genome scan in a set of rat recombinant inbred strains (RIS) originating from reciprocal crosses of SHR and normotensive Brown Norway (BN) Lx strains. This is the only set of rat RIS available to study the genetics of hypertension and its related traits. 8 Any quantitative phenotype that can be measured accurately and that displays a significant gradient across strains can be mapped in the RIS panel, irrespective of the differences between progenitor strains, 9 in this permanent replica of...

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“…Individual 10-s waveforms of systolic pressure (SP), diastolic pressure (DP), mean arterial pressure (MAP), and HR were sampled every 2 min throughout the monitoring period. To assess the impact of immobilization stress on BP and HR, BP and HR were measured continuously during 30-min immobilization in a restraining device (IITC Life Science, Woodland Hills, CA) (23). Raw data were processed by the Dataquest A.R.T Analysis program (24) and are presented as means Ϯ S.E.…”

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“…3,4,[12][13][14][15][16][17][18][19][20][21][22] They are also vital in many biological processes; 5,6,23,24 however, until our recent publications, there were no studies investigating the roles of these molecules in blood pressure (BP) regulation.…”

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“…Therefore, the stronger temperature response to immobilization in SHR could serve as a marker of stress susceptibility. Indeed, we have found the genetic determinants of this enhanced stress response in hypertensive rats and observed a strong sexual dimorphism in the SHR, the Y chromosome from hypertensive origin contributing significantly to this enhanced response (Dumas et al, 2000a). Because a similar abnormal response has also been reported in humans subjected to psychogenic stress, and because this abnormal response correlates with the future hypertensive status of these individuals, it is important 1) to characterize and to be able to recognize this stress response and 2) to employ methods of blood pressure determination devoid of this important confounder.…”

“…The higher stress response resulting can affect several pathways and organs and will contribute to the development of hypertension. Of note, the stress gene expression is enhanced in SHR as compared to WKY and Brown-Norway rats after a 1-hour immobilisation stress, and the genetic difference points to the heat-shock transcription factor hstf (Dumas et al, 2000a(Dumas et al, & 2000b. Others have reported differences in blood flow or increase in sympathetic nerve activity associated with sodium retention in SHR following stress (Yamamoto et al, 1987;Koepke & DiBona, 1985).…”