sGCα<sub>1</sub>β<sub>1</sub>attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Buys, Emmanuel; Cauwels, Anje; Raher, Michael J.; Passeri, Jonathan J.; Hobai, Ion A.; Cawley, Sharon M; Rauwerdink, Kristen M.; Thibault, Hélène; Sips, Patrick; Thoonen, Robrecht; Scherrer‐Crosbie, Marielle; Ichinose, Fumito; Brouckaert, Peter; Bloch, Kenneth D.

doi:10.1152/ajpheart.00367.2009

Cited by 43 publications

(42 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only male mice were studied. Generation of sGCα1 -/-S6 (generated on the S6 background) and sGCα1 -/-B6 mice (backcrossed 8 generations with B6 mice from The Jackson Laboratory) was described previously (18,21). WT B6 and WT S6 mice were purchased from The Jackson Laboratory and Taconic, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The F1 offspring were subsequently intercrossed (16 breeding pairs) to yield F2 offspring. MAP was measured invasively in 284 male F2 offspring at 4 months of age, as previously described (18,21). Briefly, mice were anesthetized by i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Several reports demonstrated that linkage studies in rodents represent a feasible and powerful approach to identify genetic loci and/or candidate modifier genes involved in the etiology of hypertension (31,(37)(38)(39)(40). In the current study, we sought to identify genetic variants that modify blood pressure in sGCα 1 -/-mice by taking advantage of the observation that male sGCα 1 -/-S6 but not sGCα 1 -/-B6 mice develop hypertension (18,21). Using a linkage analysis approach in 284 sGCα 1 -/-F2 mice, we identified a genomic locus (Hsgcq) on chromosome 1 (covering ≈40 Mb) that was associated with hypertension in sGCα 1 -/-mice.…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Buys¹,

Raher²,

Kirby³

et al. 2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα 1 ), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα 1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα 1 -deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling. IntroductionSystemic arterial hypertension is one of the most widespread public health problems in the developed world and the most prevalent modifiable risk factor for cardiovascular disease (CVD) in both women and men (1). The pathogenesis of essential hypertension is multifactorial, and in the vast majority of cases the etiology of hypertension is unknown. Although major advances in the treatment of hypertension have decreased CVD-related deaths over the last decade (2), many of the molecular mechanisms underlying the development of hypertension remain elusive. Genome-wide association studies (GWAS) suggest that there is a substantial heritable component to blood pressure (3, 4). Although GWAS have identified several loci associated with blood pressure in human beings, including loci containing genes that either regulate cGMP levels (4-7) or the renin-angiotensin-aldosterone system (RAAS) (8), many of the genetic factors determining blood pressure and how these factors interact remain to be identified.Renal abnormalities, such as decreased urinary sodium excretion in response to increasing renal perfusion pressure, and increased activity of the RAAS are generally considered to be a major contributor to the development of high blood pressure (9). However, other studies support the idea that hypertension can arise from primary vascular abnormalities (10, 11). The ability of NO to relax vascular smooth muscle and its essential role in the regulation of blood flow are well characterized (12, 13). Ample evidence suggests that altered NO signaling is involved in the pathogenesis of hypertension (14).One of the primary receptors for NO is soluble guanylate cyclase (sGC), a heme-containing enzyme that generates cGMP. The

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Buys¹,

Raher²,

Kirby³

et al. 2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…7B). As PTH is known to have hypotensive effects on the vasculature (18), and previous studies in rats show that PTH-induced reductions in systemic blood pressure can result in reduced glomerular blood flow (19), we assessed the effects of PTH administration on systemic blood pressure in WT and PD mice (20). Following a brief i.v.…”

Section: Effects Of Pth Analogs On Signaling In Bone and Kidney Of Wtmentioning

confidence: 99%

Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH

Maeda

Okazaki

Baron

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Agonist-induced phosphorylation of the parathyroid hormone (PTH) receptor 1 (PTHR1) regulates receptor signaling in vitro, but the role of this phosphorylation in vivo is uncertain. We investigated this role by injecting "knock-in" mice expressing a phosphorylation-deficient (PD) PTHR1 with PTH ligands and assessing acute biologic responses. Following injection with PTH (1-34), or with a unique, long-acting PTH analog, PD mice, compared with WT mice, exhibited enhanced increases in cAMP levels in the blood, as well as enhanced cAMP production and gene expression responses in bone and kidney tissue. Surprisingly, however, the hallmark hypercalcemic and hypophosphatemic responses were markedly absent in the PD mice, such that paradoxical hypocalcemic and hyperphosphatemic responses were observed, quite strikingly with the long-acting PTH analog. Spot urine analyses revealed a marked defect in the capacity of the PD mice to excrete phosphate, as well as cAMP, into the urine in response to PTH injection. This defect in renal excretion was associated with a severe, PTH-induced impairment in glomerular filtration, as assessed by the rate of FITC-inulin clearance from the blood, which, in turn, was explainable by an overly exuberant systemic hypotensive response. The overall findings demonstrate the importance in vivo of PTH-induced phosphorylation of the PTHR1 in regulating acute ligand responses, and they serve to focus attention on mechanisms that underlie the acute calcemic response to PTH and factors, such as blood phosphate levels, that influence it.calcium homeostasis | family B GPCR | phosphate homeostasis | receptor phosphorylation P arathyroid hormone (PTH) plays a critical role in regulating blood concentrations of ionized calcium by acting via its receptor, the PTH receptor 1 (PTHR1), expressed by target cells of bone and kidney. In response to decreases in blood Ca 2+ levels, PTH thus acts to promote the release of calcium from bone, and the reabsorption of calcium from the glomerular filtrate. PTH also acts to lower blood inorganic phosphate (Pi) by promoting the renal excretion of Pi into the urine. PTH acts in concert with several other calcium-and phosphate-regulating factors, including 1,25(OH) 2 -vitamin-D 3 and FGF23, as part of a tightly regulated homeostatic system of mineral ion control (1). Of note, PTH peptides injected daily at low dose can stimulate new bone formation and are thus in use to treat osteoporosis (2). Because of their calcemic actions, PTH peptides also hold promise as treatments for hypoparathyroidism (3).The PTHR1 is a class B G protein-coupled receptor (GPCR) that signals via the Gαs/cAMP/PKA and Gαq/phopholipase C (PLC)/intracellular calcium (iCa)/PKC pathways (4). In cultured cells, agonist activation of the PTHR1 induces rapid receptor internalization and signal desensitization. As for most GPCRs, the PTHR1 is phosphorylated on its C-terminal tail following agonist activation, and this phosphorylation promotes the internalization and desensitization responses, in large part...

show abstract

“…We treated our patient with nitrates until the heart recovery, aiming to improve myocardial perfusion. Buys et al reported in mice a protective effect of nitric oxide against cardiac dysfunction caused by inflammatory shock, known to interfere with mitochondrial respiration, mediated by soluble guanylate cyclase producing cyclic guanosin monophosphate 7 . Cauwels et al found that nitrite had a protective effect on mitochondrial respiration and improved cellular energetics against TNFmediated inhibition of complexes I and IV of the mitochondrial respiratory chain 8 .…”

mentioning

confidence: 99%

Surviving a Massive Sodium Azide Poisoning with Toxic Cardiomyopathy

Overtchouk¹,

Poissy²,

Thieffry³

et al. 2015

ICFJ

View full text Add to dashboard Cite

Sodium azide poisoning is rare (~50 case reports) but can be quickly fatal. A systematic review reported the fatal dose in humans to be over 10 mg/kg 1 . A 69 year-old female was admitted to our hospital for voluntary sodium azide poisoning. She ingested a massive dose of a soup spoon (15 g) of pure sodium azide powder with intention to commit suicide without any co-intoxication. Within minutes, she felt nauseous and had several vomiting. She was immediately brought to the hospital.At admission, 2 hours after the ingestion, despite the absence of hypotension she had widespread marbles on her knees and an extended recoloration time. She had no signs of cardiac insufficiency. Diaphoresis was noticed. Biology showed a balanced metabolic acidosis with (pH of 7.48, bicarbonate 17,2 mmol/L), high blood lactate (6,6 mmol/L) indicating tissue hypoxia, elevated blood glucose (2,1 g/L), normal hypersensitive troponin. The electrocardiogram (ECG) was normal. The patient was immediately treated with gastric lavage and crystalloids. Hyperlactatemia and acidosis resolved within 12 hours.On the 3rd day after the poisoning the biology showed increased hypersensitive troponine (100 ng/mL, normal < 50 ng/ mL). The ECG showed a ST-segment elevation in leads DI, DII, AVL, AVF, and V4 to V6, with reciprocal ST depression in leads AVR and V1 without any chest pain (figure 1). Contemporary blood lactate increased again (4.3 mmol/L), same as liver transaminases (3 times the normal rate) and CRP (80 mg/L). The transthoracic echocardiography showed a decreased left ventricle ejection fraction (LVEF) at 30% with no dilation. Akinesis was noted in the apex, upper third of the lateral and inferior area. The left ventricle was overall hypokinetic. Medium E/E' ratio of 12.5 pointing out elevated left ventricle filling pressure. The right ventricle and the systolic arterial pulmonary pressure were normal. There was no pericardial effusion.She was immediately transferred for emergency coronary angiography which found no clot or coronary spasm, but a 80% stenosis was noticed in the proximal section of the right coronary artery. No angioplasty was carried out. Nitrates were introduced to improve myocardial perfusion.A cardiac MRI (Magnetic Resonance Imaging) was carried out 3 weeks after the poisoning. It showed a LVEF of 52%, a slight overall hypokinesis, no pathological enhancement, thus no myocarditis or infarct sequelae. Besides it showed a circumferential pericardial effusion of moderate volume (maximum 17 millimeters facing the left ventricle).We concluded to toxic cardiomyopathy caused by sodium azide.

show abstract

sGCα₁β₁attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Cited by 43 publications

References 59 publications

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH

Surviving a Massive Sodium Azide Poisoning with Toxic Cardiomyopathy

Contact Info

Product

Resources

About

sGCα1β1attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Cited by 43 publications

References 59 publications

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH

Surviving a Massive Sodium Azide Poisoning with Toxic Cardiomyopathy

Contact Info

Product

Resources

About

sGCα₁β₁attenuates cardiac dysfunction and mortality in murine inflammatory shock models