Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Zhao, Lan; Sebkhi, Abdelkrim; Nunez, Derek J.; Long, Lu; Haley, C.S.; Szpirer, Josiane; Szpirer, Claude; Williams, Alan J.; Wilkins, Martin R.

doi:10.1161/01.cir.103.3.442

Cited by 30 publications

(29 citation statements)

References 37 publications

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“…All published heart weight/hypertrophy QTLs on chromosome 17 harbor a common interesting candidate gene, Drd1a (dopamine receptor 1a). [22][23][24][25][26][27][28][29][30][31][32][33] Overall, these results may demonstrate that rat chromosome 17 harbors major gene(s) involved in BP regulation as well as those involved in the regulation of major metabolic pathways and body homeostasis in LH rats.…”

Section: Bilusic Et Al Genetic Analysis In the Lyon Hypertensive Ratmentioning

confidence: 96%

“…Other studies have reported BP QTLs in the same region in 3 different F 2 intercrosses (Table 2). [22][23][24][25][26][27][28][29][30][31][32][33] We found that the angiotensin receptor 1a gene (Atr1a) is in this putative QTL region. All published heart weight/hypertrophy QTLs on chromosome 17 harbor a common interesting candidate gene, Drd1a (dopamine receptor 1a).…”

Section: Bilusic Et Al Genetic Analysis In the Lyon Hypertensive Ratmentioning

confidence: 99%

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Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

et al. 2004

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Abstract-The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes.We have performed a total genome scan in offspring of an F 2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat. Key Words: genetics Ⅲ linkage analysis Ⅲ metabolism Ⅲ hypertension, genetic Ⅲ rats, inbred strains Ⅲ cardiovascular diseases H uman essential hypertension and associated cardiovascular diseases are multifactorial disorders with a complex etiology, resulting from the interaction between multiple genes and environmental factors. Despite development of new genetic and genomic technologies, the genetic determinants of multifactorial disorders remain unclear. The study of animal models in discovering pathophysologic and genetic determinants of polygenetic disorders such as hypertension provides a platform of reduced heterogeneity. Currently, there exist several different genetically hypertensive rat and mouse selection models. 1 Numerous linkage studies in rats have shown that each rat chromosome contains at least 1 blood pressure (BP) quantitative trait locus (QTL; http://rgd.mcw.edu/qtls).The Lyon hypertensive (LH) rat has many features common to the human metabolic syndrome, a group of metabolic risk factors including central obesity, atherogenic dyslipidemia, elevated BP, insulin resistance or glucose intolerance, and prothrombotic and proinflamatory states. 2 Interestingly, a control strain, the Lyon normotensive (LN) rat, has been simultaneously derived from a common ancestor of the LH; the LN is genetically quite similar to the LH (85% identical based on characterization of 4328 microsatellite markers; data not shown) but phenotypically very distinct. Compared with the LN, LH rats have mild salt-sensitive hypertension and reduced life ...

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Section: Bilusic Et Al Genetic Analysis In the Lyon Hypertensive Ratmentioning

confidence: 96%

Section: Bilusic Et Al Genetic Analysis In the Lyon Hypertensive Ratmentioning

confidence: 99%

Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

et al. 2004

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“…However, variation in the pulmonary vascular response to hypoxia is well recognized, both between and within species, 16,31,54,55 and in humans the magnitude of HPV can vary ≈5-fold among individuals. 16,55 Extreme responders are at highest risk of presenting acutely on arrival at altitude with high-altitude pulmonary edema (HAPE) or over weeks, months, and years with right heart failure secondary to severe pulmonary hypertension or excessive erythrocytosis.…”

Section: Clinical Presentations From Maladaptation To Hypoxia Variatimentioning

confidence: 99%

Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease

et al. 2015

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582I t is estimated that >140 million people live above 2500 m in various regions of the world.1 There are many challenges to living at high altitude, but chronic exposure to alveolar hypoxia is prominent among them. Inspired Po 2 falls from ≈150 mm Hg at sea level to ≈100 mm Hg at 3000 m and 43 mm Hg on the summit of Everest (8400 m). 2,3 The body responds by hyperventilating, increasing resting heart rate, and stimulating red cell production in an attempt to maintain the oxygen content of arterial blood at or above sea level values.2 However, hypoxic pulmonary vasoconstriction (HPV) and vascular remodeling, together with increased erythropoiesis, place an increased pressure load on the right ventricle (RV). How well healthy humans adapt to hypoxia depends on their rate of ascent to altitude, the severity and duration of their exposure, and their genetic background. Pathophysiology of Acclimatization to Hypoxia Pulmonary Vascular Response to HypoxiaFor most mammals, including humans, a rise in pulmonary artery pressure (PAP) is an early and inevitable consequence of ascent to high altitude. Resting mean PAP increases along a parabolic curve from 15 mm Hg at 2000 m to ≈30 mm Hg at 4500 m. 4 The exceptions and interindividual variation in the magnitude of response offer a natural experiment that might provide insight into fundamental underlying mechanisms (vide infra).The initial rise in PAP on exposure to hypoxia is attributed to HPV. With chronic hypoxia, other mechanisms that likely drive vascular remodeling soon contribute to the elevated pressure ( Figure 1A). After 2 or 3 weeks of hypoxia, there is little response to rebreathing 100% oxygen, indicating a structural resistance to pulmonary blood flow rather than one based solely on increased vasomotor tone. 6 A fall in PAP on re-exposure to a normal oxygen environment is evident in rats monitored by telemetry over days after removal from a hypoxic chamber 7 ( Figure 1B) and is also documented in humans. 4,8 Pulmonary Arteriolar Vasoconstriction Dominates the Acute Pulmonary Vascular Response to HypoxiaOxygen tension is a major regulator of pulmonary vascular tone and a physiological mechanism for matching perfusion with ventilation. A fall in alveolar Po 2 is the main stimulus for HPV, but a reduction in mixed venous and bronchial arterial Po 2 may also contribute. 9 Ventilation of intact lungs with a hypoxic gaseous mixture (eg, fraction of inspired oxygen=0.10) leads to acute pulmonary vasoconstriction throughout the pulmonary vascular bed, including nonmuscular arterioles, capillaries, and veins, but is most pronounced in small pulmonary arterioles. [10][11][12][13] That said, HPV is not distributed evenly throughout the lung and lung perfusion is inhomogeneous during hypoxia.14 HPV has at least 2 phases ( Figure 1A). An initial constrictor response that starts within seconds and reaches a maximum within minutes is followed by a sustained phase, which develops after 30 to 120 minutes. 9 A transient phase of vasodilation may be observed linking the two, an...

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“…16,17 Numerous lines of clinical and experimental evidence have indicated that altered RyR-2 gene and function contribute to cardiac disorders, including catecholaminergic polymorphic ventricular tachycardia or arrhythmogenic right ventricular cardiomyopathy type 2, 15 cardiac hypertrophy, and dysfunction. 18,19 Furthermore, RyR-2 is hyperphosphorylated by protein kinase A (PKA) in HF, resulting in dissociation of FKBP12.6 from RyR-2 and Ca 2ϩ leaks from SR in diastole, which impair contractility. 16,17 Thus, alteration in RyR-2 is critically involved in abnormality of Ca 2ϩ handling and contractile dysfunction in HF.…”

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confidence: 99%

Ryanodine Receptor Type 2 Is Required for the Development of Pressure Overload-Induced Cardiac Hypertrophy

et al. 2011

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Abstract-Ryanodine receptor type 2 (RyR-2) mediates Ca 2ϩ release from sarcoplasmic reticulum and contributes to myocardial contractile function. However, the role of RyR-2 in the development of cardiac hypertrophy is not completely understood. Here, mice with or without reduction of RyR-2 gene (RyR-2 ϩ/Ϫ and wild-type, respectively) were analyzed. At baseline, there was no difference in morphology of cardiomyocyte and heart and cardiac contractility between RyR-2 ϩ/Ϫ and wild-type mice, although Ca 2ϩ release from sarcoplasmic reticulum was impaired in isolated RyR-2 ϩ/Ϫ cardiomyocytes. During a 3-week period of pressure overload, which was induced by constriction of transverse aorta, isolated RyR-2 ϩ/Ϫ cardiomyocytes displayed more reduction of Ca 2ϩ transient amplitude, rate of an increase in intracellular Ca 2ϩ concentration during systole, and percentile of fractional shortening, and hearts of RyR-2 ϩ/Ϫ mice displayed less compensated hypertrophy, fibrosis, and contractility; more apoptosis with less autophagy of cardiomyocytes; and similar decrease of angiogenesis as compared with wild-type ones. Moreover, constriction of transverse aorta-induced increases in the activation of calcineurin, extracellular signal-regulated protein kinases, and protein kinase B/Akt but not that of Ca 2ϩ /calmodulin-dependent protein kinase II, and its downstream targets in the heart of wild-type mice were abolished in the RyR-2 ϩ/Ϫ one, suggesting that RyR-2 is a regulator of calcineurin, extracellular signal-regulated protein kinases, and Akt but not of calmodulin-dependent protein kinase II activation during pressure overload. Taken together, our data indicate that RyR-2 contributes to the development of cardiac hypertrophy and adaptation of cardiac function during pressure overload through regulation of the sarcoplasmic reticulum Ca 2ϩ release; activation of calcineurin, extracellular signal-regulated protein kinases, and Akt; and cardiomyocyte survival.

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Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Cited by 30 publications

References 37 publications

Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease

Ryanodine Receptor Type 2 Is Required for the Development of Pressure Overload-Induced Cardiac Hypertrophy

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