Andreas Beyer Lab
Andreas M. Beyer is an Assistant Professor in the Departments of Medicine and Physiology at the Medical College of Wisconsin. During his training in Genetics and Physiology, he has gained detailed expertise in generating and evaluating novel approaches in genetics, molecular biology and physiology. In his time spent in the lab he performs experimental troubleshooting involving video microscopy, fluorescent microvascular imaging, generation of genetic rodent models, physiological evaluation of in vivo vascular function and blood pressure. With the support of this research group and important local and national collaborators, Andreas is using live human tissues to address important questions in vascular biology that will lead to clinically relevant findings and drive further exploration of mechanism in rodent models. His lab hopes that clinically relevant data from human tissues will enable a detailed mechanistic understanding of disease that can then be used to develop novel therapeutics and translate both diagnostics and therapies themselves to the clinic.
The Beyer lab studies the complex relationship and physiological effects of vascular stress response with and aging. We are interested in how telomerase activity contributes to the regulation of reactive oxygen species (ROS) and nitric oxide (NO) in health and disease. The role of telomerase in aging and the development of cancer are well established. The catalytic subunit of telomerase, TERT, elongates telomeres in the nucleus to prevent cellular aging and promote proliferation. A potential role in the development of cardiovascular disease (CVD), especially via the endothelium where vascular disease begins, has not been described. This novel idea is supported by a recently described non-nuclear role for TERT in regulating levels of mitochondrial derived reactive oxygen species (mtROS) in fibroblasts. A similar function in endothelial cells would position TERT as a key regulator of oxidative stress and microvascular function.
Endothelial release of NO induces flow-mediated dilation (FMD) under physiological conditions and serves to prevent vascular smooth muscle proliferation and inflammation. In subjects with coronary artery disease (CAD), however, arteriolar FMD is mediated by mtROS, specifically hydrogen peroxide (H2O2), which is a pro-inflammatory and pro-atherosclerotic dilator. We observed that activation of telomerase restores nitric oxide (NO) as the mediator of FMD in vessels from subjects with CAD, while reduction of telomerase activity (TA) in vessels from subjects without CAD activates a CAD-like phenotype. We have generated novel decoy peptides that prevent either telomerase localization to the nucleus or translocation to the mitochondria. Inhibition of nuclear transport of TERT increases cytoplasmic (including mitochondrial) telomerase localization and activity. CAD is associated with elevations in Angiotensin II (ANG II) which contribute to elevated ROS and decreased NO-mediated endothelium-dependent dilation.
Our central hypothesis is that TERT plays a critical and previously undiscovered role in maintaining physiological NO levels while simultaneously suppressing the compensatory rise in mtROS during flow in coronary vessels of both mice and humans. Preliminary data indicate that acute stimulation of telomerase activity is sufficient to maintain NO release following vascular stress, and to decrease mtROS production, suggesting a role independent of telomere shortening. We are utilizing clinically-relevant stressors such as ANG II to deduce the role of mtTERT in relation to vascular stress responses and regulation of mtROS.
Ongoing studies integrate cell culture, in vitro vascular and whole animal approaches. We are defining the effects of telomerase inhibition or activation (global and mitochondrial) on ANG II-induced endothelial dysfunction (human and mouse). Cell culture models are used to investigate important regulators of cellular redox environment (NO/ROS balance).
Systemic chemotherapy (CT), such as doxorubicin (Dox), plays a central role in cancer therapy. Anthracyclines including Dox often are the only recourse available for many cancers, including leukemia, breast, and bladder cancer. The major limitation of Dox is its acute and chronic cardiovascular (CV) toxicity. The underlying pathological mechanisms that predict susceptibility to Dox-induced adverse CV events and strategies to mitigate its toxicity without interfering with the efficacy of the treatment represents a huge clinical challenge.
CT-induced heart failure is well established; however, a major gap exists in understanding the underlying mechanisms. Recent evidence in rat models suggests that dysfunction of the microcirculation is a contributing factor via mitochondrial DNA (mtDNA) damage, both in the heart and systemically33. mtDNA damage gives rise to cell free mtDNA (cf-mtDNA) which act in a paracrine fashion to promote systemic endothelial dysfunction via activation of toll-like receptors (TLRs), invoking inflammatory responses leading to endothelial dysfunction, vascular injury, impaired myocardial perfusion, and heart failure. Interestingly, traditional biomarkers of cardiac injury (CRP, Interleukins) are not associated with adverse CV outcomes after CT61. However, mtDNA damage, elevated levels of circulating DNA, and decreased telomerase activity (TA), but not telomere length (TL), predict adverse CV events up to six years after cessation of CT61. This suggests a major non-canonical and untested role for telomerase in CT-induced cardiomyopathy. We propose that suppression of TA, a key part of Dox-induced cancer cell toxicity14, initiates CV toxicity by suppression of the protective effects of TERT, the catalytic subunit of telomerase, in the vascular system where TERT reduces mtDNA damage. TERT upregulation suppresses oxidative injury in mitochondria2, 10, 24, 36, 65, giving rise to the idea that inhibition of nuclear telomerase is critical for the anticancer effect of Dox while the preservation of mitochondrial TA is paramount to prevent Dox-induced cardiotoxicity the rate limiting step in its therapeutic window.
We hypothesize that loss of mitochondrial TERT (mtTERT) increases Dox-induced mitochondrial damage to stimulate inflammatory responses, elevates ROS, and initiates an extrusion of DNA into the circulation. Previous work has linked cf-mtDNA to mitochondrial defects and decreased endothelial function in rodent models of hypertension71; yet, no studies to date have tested the role of cf-mtDNA on endothelium-dependent vascular function after CT. Our strong preliminary data shows that cf-mtDNA, similar to Dox, induces microvascular dysfunction by elevating ROS production in a TLR-9 dependent manner. We further present evidence that activation of mtTERT or initiation of mtDNA repair mechanisms via a mitochondrial targeted endonuclease (mtEndo III) is sufficient to overcome Dox-induced endothelial dysfunction. The goal of this cross disciplinary proposal is to determine how CT elicits endothelial dysfunction with consequent heart failure.
As illustrated in Fig. 1, we hypothesize that upregulation of mtTERT can circumvent the CT-induced endothelial dysfunction by suppressing mtDNA damage and mtROS, thereby preventing the development of CT-induced microvascular dysfunction.
View Dr. Beyer's complete list of published work.
Laura Norwood Toro
Research Scientist I
Laura Norwood Toro is a Research Scientist I in the Andreas Beyer Lab. Her primary responsibility is to explore the effect of chemotherapy on cardiovascular outcomes in coronary circulation and vascular endothelium. One focus of her studies is to investigate the functions of telomerase in the nucleus versus the mitochondria. Her background is in cell biology and molecular biology.
Bill Hughes, PhD
Bill Hughes is a postdoctoral fellow in the Beyer/Gutterman Lab. Prior to starting at MCW he received his PhD from the University of Iowa. His research interests are human integrative cardiovascular physiology and vascular biology in health, aging, and chronic disease. In collaboration with Dr. Beyer and Dr. Gutterman, he is studying the cross-talk between autophagy, a basic cellular recycling process, and telomerase within the context of microvascular function in coronary artery disease (CAD). Flow-mediated dilation is predominately mediated by nitric oxide (NO) in healthy populations, but this mediator switches to hydrogen peroxide (H2O2) with CAD. Autophagy has recently been demonstrated to be sensitive to shear stress, and preliminary data from our lab indicates that inhibition of autophagy switches the mediator of FMD from NO to H2O2 in non-CAD vessels, while activation of autophagy in CAD vessels recapitulates a healthy phenotype (NO-mediated). Additionally, our lab has also demonstrated that upregulation of telomerase reduces mitochondrial release of H2O2 in vessels with CAD, restoring NO-mediated FMD. In this context, it is possible that there is significant crosstalk between pathways, with telomerase upstream of autophagy. Collectively, as numerous chronic diseases modulate both telomerase activity and autophagy it remains unknown how these two processes are inherently linked in the context of CAD.
Research Technologist II
Shelby Hader is a Research Technologist II in the Beyer/Gutterman Lab. Prior to starting at MCW she received her BA from the Lawrence University. Her primary goal is to analyze the vascular reactivity of human coronary arterioles and adipose micro vessels within different healthy and diseased patients. Some of her projects include: the cardiotoxicity of chemotherapy upon the microvasculature along with measuring the differences between fission and fusion of mitochondria in human arterioles. Additionally, Shelby provides research support for multiple projects in the lab via imaging, dissection of discarded tissue, and rat/mice colony maintenance.
Janée Terwoord is a postdoctoral fellow working with Drs Beyer and Gutterman to investigate human microvascular physiology. Prior to joining the team at MCW, Janée earned her PhD in a clinical laboratory focused on the integrative control of blood flow distribution in humans. Her research interests include the signaling mechanisms that regulate vascular tone. Currently, Janée is working to characterize the cellular mechanisms by which cancer therapeutic drugs damage the microvasculature. She is studying how mitochondrial damage induced by these drugs contributes to endothelial dysfunction, which will inform new approaches to mitigate the detrimental cardiovascular effects of anti-cancer therapy.
Research Technologist I
Micaela Young is a Research Technologist I in Dr. Gutterman’s and Dr. Beyer’s lab. She recently completed her bachelor’s degree at Marquette University with a major in Bioelectrical Engineering. Her main goal is to investigate the effect of Beta-del TERT on mitochondrial integrity and function. Additionally, she will use computational modelling and gene expression profiling to predict mitochondrial and cellular changes after changes of Beta-del TERT overexpression or knock out. She will also provide research support for projects in the lab via molecular biology techniques and computational modelling.
- Karima Ait-Aissa
- Daniela Didier
- Johnathan Ebben
- Joe Hockenberry
- Andrew D. Kadlec, PhD
- Minhi Kang
- Todd Le
- Jasmine Linn
(Durand MJ, Hader SN, Derayunan A, Zinkevich N, McIntosh JJ, Beyer AM.) Microcirculation. 2020 10;27(7):e12625 PMID: 32395853 PMCID: PMC7606774 SCOPUS ID: 2-s2.0-85090145617 05/13/2020
(Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T.) Eur Heart J. 2020 Sep 21;41(36):3462-3474 PMID: 32657324 SCOPUS ID: 2-s2.0-85089665699 07/14/2020
(Hughes WE, Beyer AM, Gutterman DD.) Basic Res Cardiol. 2020 06 06;115(4):41 PMID: 32506214 SCOPUS ID: 2-s2.0-85086002230 06/09/2020
(Hughes WE, Beyer AM, Gutterman DD.) Basic Research in Cardiology. 1 July 2020;115(4) SCOPUS ID: 2-s2.0-85086002230 07/01/2020
(Hader SN, Zinkevich N, Norwood Toro LE, Kriegel AJ, Kong A, Freed JK, Gutterman DD, Beyer AM.) Am J Physiol Heart Circ Physiol. 2019 10 01;317(4):H705-H710 PMID: 31397169 PMCID: PMC6843017 SCOPUS ID: 2-s2.0-85072508643 08/10/2019
(Durand MJ, Ait-Aissa K, Levchenko V, Staruschenko A, Gutterman DD, Beyer AM.) Cardiovasc Res. 2019 08 01;115(10):1546-1556 PMID: 30476208 PMCID: PMC6648341 SCOPUS ID: 2-s2.0-85072658081 11/27/2018
(Beyer AM, Bonini MG, Moslehi J.) Am J Physiol Heart Circ Physiol. 2019 07 01;317(1):H164-H167 PMID: 31172808 PMCID: PMC6692734 SCOPUS ID: 2-s2.0-85069238135 06/08/2019
(Ait-Aissa K, Blaszak SC, Beutner G, Tsaih SW, Morgan G, Santos JH, Flister MJ, Joyce DL, Camara AKS, Gutterman DD, Donato AJ, Porter GA Jr, Beyer AM.) Sci Rep. 2019 05 20;9(1):7623 PMID: 31110224 PMCID: PMC6527853 SCOPUS ID: 2-s2.0-85066048228 05/22/2019
(Ait-Aissa K, Heisner JS, Norwood Toro LE, Bruemmer D, Doyon G, Harmann L, Geurts A, Camara AKS, Beyer AM.) Front Cardiovasc Med. 2019;6:31 PMID: 31001540 PMCID: PMC6454001 04/20/2019
(Hughes WE, Beyer AM.) Am J Physiol Heart Circ Physiol. 2019 01 01;316(1):H183-H185 PMID: 30412440 PMCID: PMC6383357 SCOPUS ID: 2-s2.0-85059796597 11/10/2018
(Chabowski DS, Kadlec AO, Ait-Aissa K, Hockenberry JC, Pearson PJ, Beyer AM, Gutterman DD.) Br J Pharmacol. 2018 11;175(22):4266-4280 PMID: 30153326 PMCID: PMC6193883 SCOPUS ID: 2-s2.0-85054757437 08/29/2018
(Audi SH, Friedly N, Dash RK, Beyer AM, Clough AV, Jacobs ER.) Free Radic Res. 2018 Sep;52(9):1052-1062 PMID: 30175632 PMCID: PMC6298832 SCOPUS ID: 2-s2.0-85054191562 09/04/2018