Genotype-specific alterations in vascular smooth muscle cell function in cystic fibrosis piglets

Guo, Jinny J.; Stoltz, David A.; Zhu, Vivian; Volk, Kenneth A.; Segar, Jeffrey L.; McCray, Paul B.; Roghair, Robert D.

doi:10.1016/j.jcf.2013.10.009

Cited by 22 publications

(13 citation statements)

References 43 publications

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“…First, CFTR channels exist on human lung microvascular cells 27 and directly cause pulmonary vascular relaxation through CFTR channel activation 28 , 29 . Additionally, CFTR mediates vascular tone independent from its role as a chloride channel through other mechanisms including stimulating nitric oxide generation via ATP release 30 , altering lipid trafficking and vascular smooth muscle cell calcium handling 31 , 32 , and through increasing expression of vascular growth factors, including VEGF-A 33 . In addition, CFTR SNPs have previously been associated with altered flow mediated dilation and flow velocity in humans 34 .…”

Section: Discussionmentioning

confidence: 99%

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

Wells

Farris

Gosdin

et al. 2016

The Lancet Respiratory Medicine

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Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:A<1 [HR 1.66 (95%CI 1.18–2.34), P=0.004] in unadjusted analysis, but not when adjusted for sex, BMI, prior exacerbation, positive Pseudomonas status, and FEV1/FVC [HR 1.14 (95%CI 0.80–1.62), P=0.82]). Interpretation PA enlargement is prevalent in adult CF patients and is associated with acute pulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF.

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Section: Discussionmentioning

confidence: 99%

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

Wells

Farris

Gosdin

et al. 2016

The Lancet Respiratory Medicine

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“…Robert et al reported the expression of CFTR in PASMCs and demonstrated its involvement in the modulation of pulmonary arterial tone (14). In the systemic circulation, CFTR-F508del, the most common mutation underlying human CF disease, has recently been associated with diminished Ca 2+ release in vascular smooth muscle cells, decreased aortic tone, and responsiveness (15). Of specific relevance for HPV, CFTR was recently shown to directly interact with TRPC6, thus regulating TRPC6-dependent Ca 2+ influx (16).…”

Section: Significancementioning

confidence: 99%

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Tabeling¹,

Wang

et al. 2015

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

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Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca 2+ mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxiainduced TRPC6 translocation to caveolae and Ca 2+ mobilization. Ca 2+ mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase-and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P 2/4 ). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P 2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.

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“…[7] Although the pathophysiological implications of ATP2B1 gene on the development of hypertension are still unclear, results from ATP2B1 knockout mouse studies suggested that ATP2B1 may play an important role in the regulation of blood pressure[8] through alterations of calcium handling and vasoconstriction in vascular smooth muscle cells. [9]…”

Section: Introductionmentioning

confidence: 99%

Evaluation of single-nucleotide polymorphisms of transcription factor 7-like 2 and ATP2B1 genes as cardiovascular risk predictors in chronic kidney disease

Kulkarni

Lenin

Ramesh

et al. 2019

Int J App Basic Med Res

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Introduction:Cardiovascular disease (CVD) is the primary cause of morbidity and premature mortality in chronic kidney disease (CKD). The transcription factor 7-like 2 (TCF7L2) gene product TCF4 is a transcription factor that acts as a downstream effector in the canonical Wnt signaling pathway and may be important in the development of both type 2 diabetes and renal development and disease. It is, therefore, plausible that mutations in this gene could manifest themselves in reduced kidney function or kidney disease through their effects on hyperglycemia as well as independent of this mechanism. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which removes bivalent calcium ions from eukaryotic cells against very large concentration gradients and is responsible for controlling the contraction and dilation of vascular smooth muscles.Aim and Objectives:The aims of this study are (1) to evaluate single-nucleotide polymorphisms (SNPs) of TCF7L2 gene as cardiovascular risk predictors in CKD and (2) to evaluate SNPs of ATP2B1 gene as cardiovascular risk predictors in CKD.Subjects and Methods:Fifty clinically diagnosed CKD patients in the age group between 20 and 60 years of both genders were selected as cases and fifty healthy participants from the master health checkup department were selected as controls. Genomic DNA was extracted based on the spin column kit method. The DNA samples were stored at −20°C until analysis. Genotyping for TCF7L2 gene rs7903146 (C/T) and ATP2B1 gene rs11105354 (A/G) was carried out through polymerase chain reaction.Results:T allele frequency was observed in 12 controls and 23 cases (odds ratio [OR] = 2.2, 95% confidence interval [CI]: 1.0–4.7). CC genotype was observed in 38 controls and 27 cases and CT genotype in 22 cases and 12 controls. A allele was found in 38 cases and 23 controls (OR = 2, 95% CI: 1.1–3.8). The mean values of cholesterol, low-density lipoprotein, triglycerides, glucose, insulin, urea, and creatinine were high in cases when compared to controls.Conclusion:T allele of TCF7L2 gene rs7903146 (C/T) and A allele of ATP2B1 (A/G) gene rs11105354 (A/G) are associated with CVD in CKD patients.

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Genotype-specific alterations in vascular smooth muscle cell function in cystic fibrosis piglets

Cited by 22 publications

References 43 publications

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Evaluation of single-nucleotide polymorphisms of transcription factor 7-like 2 and ATP2B1 genes as cardiovascular risk predictors in chronic kidney disease

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