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A functional polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, dysfunction, and ischemia: data from the heart and soul study.

Farzaneh-Far R, Desir GV, Na B, Schiller NB, Whooley MA - PLoS ONE (2010)

Bottom Line: Renalase is a soluble enzyme that metabolizes circulating catecholamines.A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has recently been described.Further studies investigating the therapeutic implications of this polymorphism should be considered.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, San Francisco General Hospital, San Francisco, California, United States of America. rfarzanehfar@medicine.ucsf.edu

ABSTRACT

Background: Renalase is a soluble enzyme that metabolizes circulating catecholamines. A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has recently been described. The association of this polymorphism with cardiac structure, function, and ischemia has not previously been reported.

Methods: We genotyped the rs2296545 single-nucleotide polymorphism (Glu37Asp) in 590 Caucasian individuals and performed resting and stress echocardiography. Logistic regression was used to examine the associations of the Glu37Asp polymorphism (C allele) with cardiac hypertrophy (LV mass>100 g/m2), systolic dysfunction (LVEF<50%), diastolic dysfunction, poor treadmill exercise capacity (METS<5) and inducible ischemia.

Results: Compared with the 406 participants who had GG or CG genotypes, the 184 participants with the CC genotype had increased odds of left ventricular hypertrophy (OR = 1.43; 95% CI 0.99-2.06), systolic dysfunction (OR = 1.72; 95% CI 1.01-2.94), diastolic dysfunction (OR = 1.75; 95% CI 1.05-2.93), poor exercise capacity (OR = 1.61; 95% CI 1.05-2.47), and inducible ischemia (OR = 1.49, 95% CI 0.99-2.24). The Glu37Asp (CC genotype) caused a 24-fold decrease in affinity for NADH and a 2.3-fold reduction in maximal renalase enzymatic activity.

Conclusions: A functional missense polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, ventricular dysfunction, poor exercise capacity, and inducible ischemia in persons with stable coronary artery disease. Further studies investigating the therapeutic implications of this polymorphism should be considered.

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Enzymatic activity and kinetics parameters of renalase variants.Change in absorbance reflects the rate of WST-1 reduction, which is index of NADH oxidation; Glu37: glutamic acid at amino acid 37; Asp37: aspartic acid at amino acid 37; BSA, bovine serum albumin; raw data shown for a single experiment.
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pone-0013496-g002: Enzymatic activity and kinetics parameters of renalase variants.Change in absorbance reflects the rate of WST-1 reduction, which is index of NADH oxidation; Glu37: glutamic acid at amino acid 37; Asp37: aspartic acid at amino acid 37; BSA, bovine serum albumin; raw data shown for a single experiment.

Mentions: Renalase is a FAD dependent oxidoreductase, which uses NADH as a cofactor to reduce its FAD moiety. In the presence of oxygen the reduced renalase-FADH complex metabolizes subtrates such as catecholamines. Renalase has intrinsic NADH oxidase activity since, in the absence of substrates, it can convert NADH to NAD+ and generate superoxide anion as a byproduct. To test if the Glu37Asp polymorphism had any detectable functional consequence, we compared the NADH oxidase activity of the Glu37 and Asp37 variants of the recombinant renalase by measuring the rate of reduction, of the electron acceptor WST-1, as a function of NADH concentration. At all NADH concentrations tested (up to 2 mM,) Glu37 metabolized NADH at a significantly faster rate than Asp37. Figure 2 depicts the results of a representative experiment with a NADH concentration of 400 µM. Kinetics parameters were determined by fitting (non linear regression) initial rate data to the Michaelis-Menten equation. The Glu37Asp mutation caused a 24 fold increase in Km (Glu37 =  34.1±4.0 µM; Asp37 = 820±115.1 µM, p<0.000001, n = 3), and a 2.3 fold reduction in Vmax (Glu37 =  58.3±1.1 nmol/min/mg; Asp37 = 25.4±1.6 nmol/min/mg, p<0.0001, n = 3).; Figure 3.


A functional polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, dysfunction, and ischemia: data from the heart and soul study.

Farzaneh-Far R, Desir GV, Na B, Schiller NB, Whooley MA - PLoS ONE (2010)

Enzymatic activity and kinetics parameters of renalase variants.Change in absorbance reflects the rate of WST-1 reduction, which is index of NADH oxidation; Glu37: glutamic acid at amino acid 37; Asp37: aspartic acid at amino acid 37; BSA, bovine serum albumin; raw data shown for a single experiment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958117&req=5

pone-0013496-g002: Enzymatic activity and kinetics parameters of renalase variants.Change in absorbance reflects the rate of WST-1 reduction, which is index of NADH oxidation; Glu37: glutamic acid at amino acid 37; Asp37: aspartic acid at amino acid 37; BSA, bovine serum albumin; raw data shown for a single experiment.
Mentions: Renalase is a FAD dependent oxidoreductase, which uses NADH as a cofactor to reduce its FAD moiety. In the presence of oxygen the reduced renalase-FADH complex metabolizes subtrates such as catecholamines. Renalase has intrinsic NADH oxidase activity since, in the absence of substrates, it can convert NADH to NAD+ and generate superoxide anion as a byproduct. To test if the Glu37Asp polymorphism had any detectable functional consequence, we compared the NADH oxidase activity of the Glu37 and Asp37 variants of the recombinant renalase by measuring the rate of reduction, of the electron acceptor WST-1, as a function of NADH concentration. At all NADH concentrations tested (up to 2 mM,) Glu37 metabolized NADH at a significantly faster rate than Asp37. Figure 2 depicts the results of a representative experiment with a NADH concentration of 400 µM. Kinetics parameters were determined by fitting (non linear regression) initial rate data to the Michaelis-Menten equation. The Glu37Asp mutation caused a 24 fold increase in Km (Glu37 =  34.1±4.0 µM; Asp37 = 820±115.1 µM, p<0.000001, n = 3), and a 2.3 fold reduction in Vmax (Glu37 =  58.3±1.1 nmol/min/mg; Asp37 = 25.4±1.6 nmol/min/mg, p<0.0001, n = 3).; Figure 3.

Bottom Line: Renalase is a soluble enzyme that metabolizes circulating catecholamines.A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has recently been described.Further studies investigating the therapeutic implications of this polymorphism should be considered.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, San Francisco General Hospital, San Francisco, California, United States of America. rfarzanehfar@medicine.ucsf.edu

ABSTRACT

Background: Renalase is a soluble enzyme that metabolizes circulating catecholamines. A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has recently been described. The association of this polymorphism with cardiac structure, function, and ischemia has not previously been reported.

Methods: We genotyped the rs2296545 single-nucleotide polymorphism (Glu37Asp) in 590 Caucasian individuals and performed resting and stress echocardiography. Logistic regression was used to examine the associations of the Glu37Asp polymorphism (C allele) with cardiac hypertrophy (LV mass>100 g/m2), systolic dysfunction (LVEF<50%), diastolic dysfunction, poor treadmill exercise capacity (METS<5) and inducible ischemia.

Results: Compared with the 406 participants who had GG or CG genotypes, the 184 participants with the CC genotype had increased odds of left ventricular hypertrophy (OR = 1.43; 95% CI 0.99-2.06), systolic dysfunction (OR = 1.72; 95% CI 1.01-2.94), diastolic dysfunction (OR = 1.75; 95% CI 1.05-2.93), poor exercise capacity (OR = 1.61; 95% CI 1.05-2.47), and inducible ischemia (OR = 1.49, 95% CI 0.99-2.24). The Glu37Asp (CC genotype) caused a 24-fold decrease in affinity for NADH and a 2.3-fold reduction in maximal renalase enzymatic activity.

Conclusions: A functional missense polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, ventricular dysfunction, poor exercise capacity, and inducible ischemia in persons with stable coronary artery disease. Further studies investigating the therapeutic implications of this polymorphism should be considered.

Show MeSH
Related in: MedlinePlus