The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

Nabika, Toru; Ohara, Hirotaka; Kato, Norihiro; Isomura, Minoru

doi:10.1038/hr.2012.30

Cited by 39 publications

(36 citation statements)

References 52 publications

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“…In addition, the double congenic strains established in this study will provide a good model to explore biological mechanisms underlying the stroke susceptibility in SHRSP. 12 Further narrowing down of the congenic regions and intensive functional analyses on the congenic strains would be required to identify the causal mutations.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of molecular mechanisms, such as context-dependent modification of gene expression by epigenetic mechanisms, microRNA, promoter/ intronic/intergenic mutations, and gene-gene interactions, may influence functions of genes. 12,23,25 However, a series of extensive studies are essential to clarify the complex biological processes potentially involving Nedd4l and other candidate genes.…”

Section: Discussionmentioning

confidence: 99%

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Two Genomic Regions of Chromosomes 1 and 18 Explain Most of the Stroke Susceptibility Under Salt Loading in Stroke-Prone Spontaneously Hypertensive Rat/Izm

Gandolgor

Ohara²,

Cui³

et al. 2013

Hypertension

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T he stroke-prone spontaneously hypertensive rat (SHRSP) genetically has severe hypertension and cerebral stroke. 1 This strain has been thought to be a good model for cerebral hemorrhage and cerebral small vessel diseases, such as lacunar infarction and deep white matter hyperintensity, at least in some aspects of their pathology.2-5 Accordingly, information about the genetic mechanisms underlying cerebral stroke in SHRSP may provide important clues to understand the pathogenesis of cerebrovascular diseases based on severe hypertension. [3][4][5] Several studies on genetic susceptibility to stroke have been performed in SHRSP; Rubattu et al 6,7 identified quantitative trait loci (QTLs) for stroke latency on chromosomes (chr) 1, 4, and 5 using a F2 cross between SHRSP/Bbb and SHR/ Bbb, of which the QTL on chr 1 was confirmed in congenic rats. Jeffs et al 8 performed a QTL analysis on infarction volume after middle-cerebral artery occlusion using a F2 cross between SHRSP/Gcrc and WKY/Gcrc and found a QTL on chr 5. Despite these pioneering works, the genetic mechanisms behind the stroke susceptibility in SHRSP have not been clarified yet.Here, we therefore performed a QTL analysis on stroke susceptibility in SHRSP/Izm. As a quantitative trait to evaluate stroke susceptibility, we used stroke latency under salt loading as in a previous study with a slight modification 6 ; the incidence of stroke differs greatly between SHRSP and SHR under salt loading, 1,6 which implies that salt-sensitive mechanisms are the key to understand the susceptibility to stroke in this model.In addition, baseline blood pressure (BP) of SHRSP/Izm differs significantly from that of SHR/Izm, which was in contrast to comparisons between SHRSP/Bbb and SHR/Bbb. 1,6 This raises the possibility that another QTL for baseline BP would be identified when SHRSP and SHR of the Izm colony were used in the analysis.Consequently, we performed a QTL analysis on stroke latency under salt loading, as well as on BP before and after salt loading. In this study, we successfully identified 2 major QTLs for the stroke latency in SHRSP/Izm on chr 1 and 18 and confirmed their effects in reciprocal single and double congenic strains. Furthermore, a comprehensive genotype analysis in substrains of SHRSP and SHR in the target regions Abstract-To clarify the genetic mechanisms of stroke susceptibility in the stroke-prone spontaneously hypertensive rat (SHRSP), a quantitative trait locus (QTL) analysis was performed. Using 295 F2 rats of a cross between SHRSP/Izm and SHR/Izm, 2 major QTLs for stroke latency under salt loading were identified on chromosomes (chr) 1 and 18. Evaluation of 6 reciprocal single and double congenic rats for these QTLs showed that substitution of the SHRSP for the SHR fragment at the chr 1 and 18 QTLs increased the relative risk for stroke by 8.4 and 5.0, respectively. The combined effect of the 2 QTLs was 10× greater than that of the background genome (by Cox hazard model). Blood pressure monitoring by radio telemetry indicated that th...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Two Genomic Regions of Chromosomes 1 and 18 Explain Most of the Stroke Susceptibility Under Salt Loading in Stroke-Prone Spontaneously Hypertensive Rat/Izm

Gandolgor

Ohara²,

Cui³

et al. 2013

Hypertension

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“…Blood pressure begins to rise between 5 and 6 weeks of age in SHR and becomes fully established around 15–20 weeks of age [52]. The closely related stroke prone SHR (SHRSP), displays more severe hypertensive phenotype than the SHR, in addition to spontaneous strokes and salt sensitivity [53,54]. …”

Section: Experimental Models Of Hypertensionmentioning

confidence: 99%

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

Delles

Carrick

Graham

et al. 2018

Expert Review of Proteomics

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Introduction: Hypertension is a complex and multifactorial cardiovascular disorder. With different mechanisms contributing to a different extent to an individual’s blood pressure, the discovery of novel pathogenetic principles of hypertension is challenging. However, there is an urgent and unmet clinical need to improve prevention, detection, and therapy of hypertension in order to reduce the global burden associated with hypertension-related cardiovascular diseases.Areas covered: Proteomic techniques have been applied in reductionist experimental models including angiotensin II infusion models in rodents and the spontaneously hypertensive rat in order to unravel mechanisms involved in blood pressure control and end organ damage. In humans proteomic studies mainly focus on prediction and detection of organ damage, particularly of heart failure and renal disease. While there are only few proteomic studies specifically addressing human primary hypertension, there are more data available in hypertensive disorders in pregnancy, such as preeclampsia. We will review these studies and discuss implications of proteomics on precision medicine approaches.Expert commentary: Despite the potential of proteomic studies in hypertension there has been moderate progress in this area of research. Standardized large-scale studies are required in order to make best use of the potential that proteomics offers in hypertension and other cardiovascular diseases.

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“…The availability of an inbred genetically homogenous animal model represents a great challenge for the discovery of genes contributing to both hypertension and to the related vascular damage [25]. First of all, a specific genetic background was shown to determine development of hypertension in SHRSP [26–29].…”

Section: Genetic Studies Of Tod In Shrspmentioning

confidence: 99%

Mitochondrial Dysfunction Contributes to Hypertensive Target Organ Damage: Lessons from an Animal Model of Human Disease

Rubattu

Stanzione

Volpe

2016

Oxidative Medicine and Cellular Longevity

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Mechanisms underlying hypertensive target organ damage (TOD) are not completely understood. The pathophysiological role of mitochondrial oxidative stress, resulting from mitochondrial dysfunction, in development of TOD is unclear. The stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable model of human hypertension and of its vascular consequences. Pathogenesis of TOD in SHRSP is multifactorial, being determined by high blood pressure levels, high salt/low potassium diet, and genetic factors. Accumulating evidence points to a key role of mitochondrial dysfunction in increased susceptibility to TOD development of SHRSP. Mitochondrial abnormalities were described in both heart and brain of SHRSP. Pharmacological compounds able to protect mitochondrial function exerted a significant protective effect on TOD development, independently of blood pressure levels. Through our research efforts, we discovered that two genes encoding mitochondrial proteins, one (Ndufc2) involved in OXPHOS complex I assembly and activity and the second one (UCP2) involved in clearance of mitochondrial ROS, are responsible, when dysregulated, for vascular damage in SHRSP. The suitability of SHRSP as a model of human disease represents a promising background for future translation of the experimental findings to human hypertension. Novel therapeutic strategies toward mitochondrial molecular targets may become a valuable tool for prevention and treatment of TOD in human hypertension.

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The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

Cited by 39 publications

References 52 publications

Two Genomic Regions of Chromosomes 1 and 18 Explain Most of the Stroke Susceptibility Under Salt Loading in Stroke-Prone Spontaneously Hypertensive Rat/Izm

Two Genomic Regions of Chromosomes 1 and 18 Explain Most of the Stroke Susceptibility Under Salt Loading in Stroke-Prone Spontaneously Hypertensive Rat/Izm

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

Mitochondrial Dysfunction Contributes to Hypertensive Target Organ Damage: Lessons from an Animal Model of Human Disease

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