Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension

Oxlund, Christina Stolzenburg; Cangemi, Claudia; Henriksen, Jan Erik; Jacobsen, I.A.; Gram, Jeppe; Schousboe, Karoline; Tarnow, Lise; Argraves, W. Scott; Rasmussen, Lars Melholt

doi:10.1038/jhh.2014.27

Cited by 11 publications

(7 citation statements)

References 26 publications

(34 reference statements)

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“…Moreover, fibulin-1 up-regulation is linked with increased stiffness 56 and kidney disease 52 , whilst its down-regulation is related to aortic dissection 57 , 58 . Fibulin-1 levels are also affected by drug interventions, so patients treated with spironolactone show reduced levels in parallel with regression of vascular remodelling 59 .…”

Section: Discussionmentioning

confidence: 99%

The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

Yasmin

Maskari

McEniery

et al. 2018

Sci Rep

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Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

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Section: Discussionmentioning

confidence: 99%

The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

Yasmin

Maskari

McEniery

et al. 2018

Sci Rep

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“…6 Increased plasma fibulin-1 concentrations were found in diabetic participants with erectile dysfunction than in those without erectile dysfunction. 8 Human coronary artery atherosclerotic lesions presented strong deposition of fibulin-1, which demonstrate the pathophysiological effects of fibulin-1 in atherosclerosis. 9 Recently, fibulin-1 was found to inhibit angiogenesis and suppress tumor growth.…”

Section: Introductionmentioning

confidence: 89%

“…In addition, serum fibulin-1 was correlated with plasma glucose levels which was evaluated by hemoglobin A(1c) 6. Increased plasma fibulin-1 concentrations were found in diabetic participants with erectile dysfunction than in those without erectile dysfunction 8. Human coronary artery atherosclerotic lesions presented strong deposition of fibulin-1, which demonstrate the pathophysiological effects of fibulin-1 in atherosclerosis 9.…”

Section: Introductionmentioning

confidence: 97%

Serum and Vitreous Fibulin-1 Concentrations in Patients with Diabetic Retinopathy

Tian

Wang

Wei

et al. 2016

Journal of Investigative Medicine

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Fibulin-1, an extracellular matrix glycoprotein, is closely correlated with angiogenesis. The purpose of this investigation is to determine serum and vitreous fibulin-1 concentrations in diabetic retinopathy (DR). This cross-sectional investigation was carried out in a population of 154 diabetic patients (54 without DR, 42 with non-proliferative diabetic retinopathy (NPDR) and 58 with proliferative diabetic retinopathy (PDR)) and 49 control subjects. The diabetic group showed higher serum and vitreous fibulin-1 concentrations than the controls. Serum and vitreous fibulin-1 concentrations in PDR patients were significantly elevated compared with those in the other 3 groups. NPDR patients showed elevated levels of serum and vitreous fibulin-1 concentrations compared with patients without DR. Logistic regression analysis revealed that serum and vitreous fibulin-1 were risk factors for developing DR. Pearson correlation analysis showed that serum fibulin-1 was correlated with systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose and vitreous fibulin-1. Furthermore, Pearson correlation analysis showed that vitreous fibulin-1 was correlated with SBP, DBP, high-density lipoprotein cholesterol and serum fibulin-1. Serum and vitreous fibulin-1 concentrations are elevated under DR condition.

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“…For the test cohort, we used data from an RCT conducted in 4 centers in Denmark. 16 Subjects included were diagnosed with resistant hypertension and type 2 diabetes, ranging in age from 18 to 75 years, and receiving 3 or more antihypertensive drugs including a diuretic and an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. At baseline, subjects were randomly assigned to double-blind treatment with spironolactone 25 mg or matching placebo.…”

Section: Methodsmentioning

confidence: 99%

Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes

Mulder

Perco

Oxlund

et al. 2020

Translational Research

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The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in subjects with diabetic kidney disease, albeit with a large variability between individuals. Identifying novel biomarkers that predict response to therapy may help to tailor spironolactone therapy. We aimed to identify a set of metabolites for prediction of albuminuria response to spironolactone in subjects with type 2 diabetes. Systems biology molecular process analysis was performed a priori to identify metabolites linked to molecular disease processes and drug mechanism of action. Individual subject data and urine samples were used from 2 randomized placebo controlled double blind clinical trials (NCT01062763, NCT00381134). A urinary metabolite score was developed to predict albuminuria response to spironolactone therapy using penalized ridge regression with leave-one-out cross validation. Bioinformatic analysis identified a set of 18 metabolites linked to a diabetic kidney disease molecular model and potentially affected by spironolactone mechanism of action. Spironolactone reduced UACR relative to placebo by median À42% (25th to 75% percentile À65 to 6) and À29% (25th to 75% percentile À37 to À1) in the test and replication cohorts, respectively. In the test cohort, UACR reduction was higher in the lowest tertile of the baseline urinary metabolite score compared with middle and upper tertiles À58% (25th to 75% percentile À78 to 33), À28% (25th to 75% percentile À46 to 8), À40% (25th to 75% percentile À52% to 31), respectively, P = 0.001 for trend). In the replication cohort, UACR reduction was À54% (25th to 75% percentile À65 to À50), À41 (25th to 75% percentile À46% to 30), and À17% (25th to 75% percentile À36 to 5), respectively, P = 0.010 for trend). We identified a set of 18 urinary metabolites through systems biology to predict albuminuria response to spironolactone in type 2 diabetes. These data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine.

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Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension

Cited by 11 publications

References 26 publications

The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

Serum and Vitreous Fibulin-1 Concentrations in Patients with Diabetic Retinopathy

Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes

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