Research Spotlight

Posted May 15th 2019

Arterial Stiffness in the Heart Disease of CKD.

Peter McCullough M.D.

Peter McCullough M.D.

Zanoli, L., P. Lentini, M. Briet, P. Castellino, A. A. House, G. M. London, L. Malatino, P. A. McCullough, D. P. Mikhailidis and P. Boutouyrie (2019). “Arterial Stiffness in the Heart Disease of CKD.” J Am Soc Nephrol Apr 30. [Epub ahead of print].

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CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.


Posted May 15th 2019

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Walters, D. C., E. Arning, T. Bottiglieri, E. E. W. Jansen, G. S. Salomons, M. N. Brown, M. A. Schmidt, G. R. Ainslie, J. B. Roullet and K. M. Gibson (2019). “Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues.” Neurochem Int 125: 151-162.

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The anticonvulsant vigabatrin (VGB; Sabril(R)) irreversibly inhibits GABA transaminase to increase neural GABA, yet its mechanism of retinal toxicity remains unclear. VGB is suggested to alter several amino acids, including homocarnosine, beta-alanine, ornithine, glycine, taurine, and 2-aminoadipic acid (AADA), the latter a homologue of glutamic acid. Here, we evaluate the effect of VGB on amino acid concentrations in mice, employing a continuous VGB infusion (subcutaneously implanted osmotic minipumps), dose-escalation paradigm (35-140mg/kg/d, 12 days), and amino acid quantitation in eye, visual and prefrontal cortex, total brain, liver and plasma. We hypothesized that continuous VGB dosing would reveal numerous hitherto undescribed amino acid disturbances. Consistent amino acid elevations across tissues included GABA, beta-alanine, carnosine, ornithine and AADA, as well as neuroactive aspartic and glutamic acids, serine and glycine. Maximal increase of AADA in eye occurred at 35mg/kg/d (41+/-2nmol/g (n=21, vehicle) to 60+/-8.5 (n=8)), and at 70mg/kg/d for brain (97+/-6 (n=21) to 145+/-6 (n=6)), visual cortex (128+/-6 to 215+/-19) and prefrontal cortex (124+/-11 to 200+/-13; mean+/-SEM; p<0.05), the first demonstration of tissue AADA accumulation with VGB in mammal. VGB effects on basic amino acids, including guanidino-species, suggested the capacity of VGB to alter urea cycle function and nitrogen disposal. The known toxicity of AADA in retinal glial cells highlights new avenues for assessing VGB retinal toxicity and other off-target effects.


Posted May 15th 2019

The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Tian, W., Z. Ye, S. Wang, M. A. Schulz, J. Van Coillie, L. Sun, Y. H. Chen, Y. Narimatsu, L. Hansen, C. Kristensen, U. Mandel, E. P. Bennett, S. Jabbarzadeh-Tabrizi, R. Schiffmann, J. S. Shen, S. Y. Vakhrushev, H. Clausen and Z. Yang (2019). “The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells.” Nat Commun 10(1): 1785.

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Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of alpha-galactosidase A in a Fabry disease mouse model, and find that an alpha2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.


Posted May 15th 2019

Longitudinal Changes in Allostatic Load during a Randomized Church-based, Lifestyle Intervention in African American Women.

Heather Kitzman Ph.D.

Heather Kitzman Ph.D.

Tan, M., A. Mamun, H. Kitzman and L. Dodgen (2019). “Longitudinal Changes in Allostatic Load during a Randomized Church-based, Lifestyle Intervention in African American Women.” Ethn Dis 29(2): 297-308.

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Introduction: African American (AA) women have disproportionately higher risk of cardiovascular disease than White women, which may be explained by the uniquely higher allostatic load (AL) found in AA women. No studies have tested the effect of lifestyle interventions on AL in AA women. Our objectives were to assess the change in allostatic load following a lifestyle intervention and explore the roles of lifestyle behaviors and socioeconomic factors on allostatic load change. Methods: Participants were non-diabetic (mean age and SD: 48.8+/-11.2 y) AA women (n=221) enrolled in a church-based, cluster randomized trial testing a standard diabetes prevention program (DPP) and a faith-enhanced DPP with 4-months of follow-up. We assessed the relationships of changes in diet, physical activity, neighborhood disadvantage, individual socioeconomic factors, and other lifestyle variables to changes in AL at 4-months using a multilevel multinomial logistic regression model. Results: Average AL decreased (-.13+/-.99, P=.02) from baseline to 4-months. After adjusting for other variables, a high school education or less (OR:.1, CI:.02-.49) and alcohol use (OR: .31, CI: .09-.99) contributed to increased AL. Living in a disadvantaged neighborhood was responsible for increased AL, though it was not statistically significant. There were no statistically significant associations between AL and other health behavior changes. Conclusions: Lower education levels may dampen the benefits of lifestyle interventions in reducing AL. Although a significant reduction in AL was found after participation in a lifestyle intervention, more research is needed to determine how lifestyle behaviors and socioeconomic factors influence AL in AA women.


Posted May 15th 2019

Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.

Howard Huang M.D.

Howard Huang M.D.

Tague, L. K., D. E. Byers, R. Hachem, D. Kreisel, A. S. Krupnick, H. S. Kulkarni, C. Chen, H. J. Huang and A. Gelman (2019). “Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.” Pharmacogenomics J Apr 17. [Epub ahead of print].

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Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (>/=A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.