AJP-Heart and Circulatory Physiology Podcast

Txnip C247S Mutation Improves Cardiac Function in Diabetes

This is a story about a good guy (thioredoxin) vs. a bad guy (Txnip). Consulting Editor Paras Mishra (University of Nebraska Medical Center) interviews lead author Jun Yoshioka (City University of New York) and expert Rebecca Ritchie (Monash University) about the latest research by Yoshioka and co-authors. As the underlying basis of diabetic cardiomyopathy remains unclear, Mukai et al. focused on the pathway connecting hyperglycemia to oxidative stress. Thioredoxin is an antioxidant molecule which uses catalytic sites at cysteine 32 and 35 to reduce target proteins and detoxify oxidative stress. The villain Txnip, an endogenous inhibitor of thioredoxin and its antioxidative properties, acts as a pro-oxidant. A high level of extracellular glucose strongly upregulates Txnip. “If glucose induces Txnip, and Txnip is a bad guy killing cells, then the obvious question is: does Txnip mediate diabetes-induced cellular damage?” explains Yoshioka. What’s the answer? Listen now.

 

Nobuhiro Mukai, Yoshinobu Nakayama, Syed Amir Abdali, Jun Yoshioka Cardiomyocyte-specific Txnip C247S mutation improves left ventricular functional reserve in streptozotocin-induced diabetic mice Am J Physiol Heart Circ Physiol, published June 4, 2021. DOI: 10.1152/ajpheart.00174.2021

Maternal Vaping Impairs Vascular Function in the Offspring

Does maternal vaping cause brain blood vessels to behave abnormally in offspring? The short answer: yes. Consulting Editor Junie Paula Warrington (University of Mississippi Medical Center) interviews authors Mark Olfert and Paul Chantler (both at West Virginia University School of Medicine), along with expert Alex Carll (University of Louisville) about the latest groundbreaking study by Burrage et al. The authors set out to understand whether exposing pregnant female rats to a low daily dose of e-cigarette aerosol—with or without nicotine—would result in middle cerebral artery dysfunction in the offspring. In this unique study design, the offspring themselves were never directly exposed to e-cigarettes. Olfert, Chantler and co-authors then assessed vascular function in arteries from the brain in pups at multiple postnatal time-points, and found the offspring had significant reduction in the ability of the middle cerebral artery to relax (or vasodilate) when they needed to. The same levels of dysfunction were found in offspring whose mothers were exposed to vaping with nicotine added to the base e-liquid, as well as offspring of mothers who were exposed to vaping without nicotine in the base e-liquid. This data suggested that some component of the e-liquid other than nicotine (such as flavors or base solution) accounted for the dysfunction that was created. What’s more, the authors discovered that the cerebrovascular dysfunction did not resolve over time. Adult rats, even 7 months after birth, displayed similar levels of impairment as the 1-month-old rat pups. This research has sweeping public health implications for those considering vaping as an alternative to smoking when pregnant. Listen now.

 

E.N. Burrage, Eiman Aboaziza, Lance Hare, Sarah Reppert, Joshua Moore, William T. Goldsmith, Eric E. Kelley, Amber Mills, Duaa Dakhlallah, Paul D. Chantler, I. Mark Olfert Long Term Cerebrovascular Dysfunction in the Offspring from Maternal Electronic Cigarette Use during Pregnancy Am J Physiol Heart Circ Physiol, published June 25, 2021. DOI: doi.org/10.1152/ajpheart.00206.2021

Vascular Reactivity in High Fat Fed Dahl SS

Why does obesity cause hypertension in some individuals but not others? Consulting Editor Dr. Shawn Bender (University of Missouri) interviews authors Stephanie Watts and Greg Fink (both of Michigan State University), along with expert Andreas Beyer (Medical College of Wisconsin), about a new study by Watts et al. Fink and Watts have had a prolific research collaboration for over 20 years investigating the physiology and pharmacology of hypertension. In recent years they have focused on the genetically hypertensive-prone Dahl salt-sensitive rat, which becomes hypertensive on a high fat diet, and the vascular and perivascular mechanisms contributing to this form of hypertension. Zeroing in on endothelial function, basic hyper-reactivity, and perivascular adipose tissue (PVAT) in aortas of Dahl SS rats fed a high fat diet, the authors found vascular dysfunction was more prevalent in males vs. females. Watts and Fink want you to reconsider PVAT as a critically important part of the vasculature, not simply a secretor of anti-contractile substances. Why? Listen now.

 

Stephanie W. Watts, Emma S. Darios, G. Andres Contreras, Hannah Garver, Gregory D. Fink Male and Female High Fat Fed Dahl SS rats are largely protected from vascular dysfunctions: PVAT contributions reveal sex differences. Am J Physiol Heart Circ Physiol, published June 14, 2021. DOI: doi.org/10.1152/ajpheart.00131.2021

Testosterone and Exercise in Middle-to-Older Aged Men

What is the impact of testosterone and exercise on fitness, body composition and strength in otherwise healthy middle-to-older aged men with mild testosterone deficiency? Associate Editor Jason Carter (Montana State University) interviews first author Lauren Chasland (University of Western Australia) and expert Megan Wenner (University of Delaware) about the new study by Chasland et al. Using a rigorous experimental approach which examined the effects of testosterone and exercise independently and in combination over a 12-week timeframe, Chasland and co-authors found that exercise alone was the primary driver of improved aerobic capacity. When assessing impact on body composition, the authors also saw greater decreases in total fat mass in the exercise-only group compared to the testosterone-only and testosterone + exercise groups. However, testosterone alone did increase leg lean mass, a result the authors think may have possible clinical translation for men unable to exercise due to disease or disability. Why did Chasland and collaborators choose a testosterone cream as their T-treatment modality? Did the exercise protocol—a circuit training routine combining cycling and resistance exercise—have an impact on the results? Listen as our experts unpack yet more evidence pointing to exercise as a potent treatment for sex hormone deficiency in aging adults.

 

Lauren C. Chasland, Bu B. Yeap, Andrew J. Maiorana, Yi X. Chan, Barbara A. Maslen, Brian R. Cooke, Lawrence Dembo, Louise H. Naylor, Daniel J. Green Testosterone and exercise: Effects on fitness, body composition and strength in middle-to-older aged men with low-normal serum testosterone levels   Am J Physiol Heart Circ Physiol, published May 3, 2021. DOI: 10.1152/ajpheart.00010.2021

Soluble Guanylate Cyclase, Intrauterine Growth Restriction, and Cardiovascular Risk

Does stimulation of the soluble guanylate cyclase pathway in late gestation improve intrauterine growth restriction in a reduced uterine perfusion pressure (RUPP) rat model of placental ischemia? In our latest podcast, Stella Goulopoulou (University of North Texas Health Science Center) interviews authors Barbara Alexander and Laura Coats (University of Mississippi Medical Center), along with expert Chris Banek (University of Arizona), about new research by Coats et al. The authors focused specifically on late gestation (day 20 to birth), which provided unique insights when compared to previous work investigating intrauterine growth restriction (IUGR) from gestation day 14 to gestation day 20. After stimulating the soluble guanylate cyclase (sGC) pathway, the authors found neither birth weight nor asymmetrical growth was improved in male offspring. In addition, the IUGR programmed male offspring, who were exposed to stimulation of the sGC pathway during late gestation, continued to develop hypertension at 4 months of age. Many preclinical studies show the benefits of sGC stimulation to the mother early in gestation and assume long-term benefit to the offspring. This work by Coats et al. is both surprising and clinically relevant to the preeclampsia research field, highlighting the crucial need for intervention late in gestation during critical fetal organ development and follow-up after birth. Where does the field go from here? Listen now.

 

Laura E. Coats, Bhavisha A. Bakrania, Daniel R. Bamrick-Fernandez, Allison M. Ariatti, Adam Z. Rawls, Norma B. Ojeda, Barbara T. Alexander Soluble guanylate cyclase stimulation in late gestation does not mitigate asymmetric intrauterine growth restriction or cardiovascular risk induced by placental ischemia in the rat Am J Physiol Heart Circ Physiol, published May 3, 2021. DOI: 10.1152/ajpheart.00033.2021

Racial & Socioeconomic Determinants of the Cardiac Epigenome

Can epigenetic analysis of DNA methylation in the myocardial genome be used to evaluate individual differences in response to treatment among heart failure patients? Consulting Editor Dr. Nisha Charkoudian (U.S. Army Research Institute of Environmental Medicine) interviews lead author Dr. Adam Wende (University of Alabama at Birmingham, Birmingham) and expert Dr. Bradford Hill (University of Louisville) about the innovative new study by Pepin et al. The authors studied human heart tissue obtained from heart failure patients during left ventricular assist device (LVAD) placement surgery. Wende and co-authors found that one of the strongest signals in the epigenetic mark DNA methylation was differentially regulated by self-reported race, identifying specific patterns in patients who self-identified as either African American or Caucasian. Long term outcomes were found to be significantly worse in the patient cohort self-identified as African American. Can the epigenetic changes uncovered by the authors help explain why African Americans have a higher susceptibility to heart failure? Listen and find out.

 

Mark E. Pepin, Chae-Myeong Ha, Luke A. Potter, Sayan Bakshi, Joseph P. Barchue, Ayman Haj Asaad, Steven M. Pogwizd, Salpy V. Pamboukian, Bertha A. Hidalgo, Selwyn M. Vickers, Adam R. Wende Racial and socioeconomic disparity associates with differences in cardiac DNA methylation among men with end-stage heart failure Am J Physiol Heart Circ Physiol, published May 7, 2021. DOI: doi.org/10.1152/ajpheart.00036.2021

Macrophage Regulation of Matrix Remodeling

As we uncover in our latest podcast episode, a meta-analysis of multiple RNA sequencing datasets with different data types leads to truly novel insights. Listen as Consulting Editors Ganesh Halade (University of South Florida) and Taben Hale (University of Arizona) interview authors Adam Engler and Alex Whitehead (University of California, San Diego) about their unique meta-analysis of RNA sequencing data which compared postnatal day 1 and day 8 hearts post-MI. The authors identified two distinct data clusters—an infarct cluster and a sham control cluster—and identified 37 genes which are critically involved in connecting fibroblasts to macrophages in the cardiac remodeling process. Because the authors did not take an either/or approach, and instead focused on both macrophages and fibroblasts, their meta-analysis connected the dots between inflammation and scar formation gene networks. “I think this is a very good example of the sum being greater than the parts,” explained Engler. This innovative work highlights several specific inflammatory processes critical to post-MI remodeling. What cellular and molecular pathways do the authors think should be targeted for therapeutic success? Listen and learn more.

 

Alexander J. Whitehead and Adam J. Engler Regenerative Crosstalk between Cardiac Cells and Macrophages  Am J Physiol Heart Circ Physiol, published March 26, 2021.
DOI: doi.org/10.1152/ajpheart.00056.2021

Behind the Bench Episode 8

What do an undergraduate degree in history, the transcription factor Forkhead box class O1 (FoxO1), and maternity leave have in common? In this new episode of our Behind the Bench podcast, host Lisandra de Castro Bras (East Carolina University) and her new co-host Charlotte Usselman (McGill University) interview lead author Kate Weeks (Baker Heart and Diabetes Institute) about a new study by Weeks and co-authors which shows FoxO1 is a critical mediator of exercise-induced cardiac hypertrophy. We reached out to Kate to get the story behind her research, because we know how critically important it is for women scientists to hear from other women scientists about balancing scientific research and life outside the lab. Kate discusses the implications of her study in considering FoxO1 as a target for treating heart disease, and she also discusses the implications of maternity leave on maintaining her career as a research scientist. Interspersed in this engaging and enlightening conversation about Kate’s research are life lessons about planning your career path, taking family leave from work, inquiring about childcare at conferences, and so much more. Listen now.

 

Kate L. Weeks,Yow Keat Tham, Suzan G. Yildiz, Yonali Alexander, Daniel G. Donner, Helen Kiriazis, Claudia A. Harmawan, Amy Hsu, Bianca C. Bernardo, Aya Matsumoto, Ronald A. DePinho, E. Dale Abel, Elizabeth A. Woodcock, Julie R. McMullen FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K  Am J Physiol Heart Circ Physiol, published April 7, 2021.
DOI: doi.org/ 10.1152/ajpheart.00838.2020

Perivascular Nerve Dysfunction in Inflammatory Bowel Disease

What is the effect of vascular function in the pathogenesis of Inflammatory Bowel Disease (IBD)? According to Centers for Disease Control data, there are approximately 3 million people with IBD in the U.S. population, with more than 7,000 new cases of IBD diagnosed every year. IBD patients are at greater risk for developing cardiovascular disease compared to age-matched peers. Listen as Consulting Editor Camilla Wenceslau (University of Toledo) interviews senior author Erika Boerman (University of Missouri) and expert Pooneh Bagher (Texas A&M Health Science Center) about this novel study by Norton et al. Decreased blood flow to the gut is a diagnostic hallmark of IBD, and sensory neurotransmitters calcitonin gene-related peptide (CGRP) and substance P are considered biomarkers of IBD. Using pressure myography to study mesenteric arteries in an interleukin-10 knockout mouse model, Boerman and collaborators investigated the activation of perivascular sensory nerves, which control gastrointestinal tract blood flow. When Boerman and co-authors first blocked substance P receptors and then stimulated sensory nerves, sensory vasodilation was rescued in the IBD vessels. A surprising finding was that the substance P pathway seemed to interfere with the CGRP pathway, preventing normal sensory vasodilation. Does Boerman estimate that an influx of immune cells into the gut, interacting with sensory neurotransmitters, is a factor in IBD pathogenesis? Listen as these experts discuss the mechanisms that impact reduced blood flow and tissue ischemia which leads to IBD, and the unanswered questions which may help to unravel the link between IBD and cardiovascular disease.

 

Charles E. Norton, Elizabeth A. Grunz-Borgmann, Marcia L. Hart, Benjamin W. Jones, Craig L. Franklin, Erika M. Boerman Role of perivascular nerve and sensory neurotransmitter dysfunction in inflammatory bowel disease   Am J Physiol Heart Circ Physiol, published April 22, 2021. DOI: doi.org/10.1152/ajpheart.00037.2021

Inorganic Arsenic Induces Cardiac Hypertrophy

Does inorganic arsenic in drinking water lead to cardiac hypertrophy? In this episode, host Dominic Del Re (Rutgers New Jersey Medical School) interviews lead author Mark Kohr (Johns Hopkins University) and expert Nicole Purcell (Huntington Medical Research Institutes) about the new study by Kohr and colleagues, which studied the effects of an environmentally-relevant level of inorganic arsenic in the drinking water of male and female mice. Kabir et al were inspired by the public health crisis in Bangladesh caused by arsenic contaminated drinking water. In their study the authors found increased systolic blood pressure, increased LV mass and wall thickness, and induction of the fetal gene program in male mice, but not in female mice. Kohr and co-authors found arsenic promoted calcineurin NFAT signaling but did not disrupt nitric oxide-dependent mechanisms of cardioprotection. The authors uncover sex differences in the cardiovascular response to arsenic, as well as a clear mechanistic link between this environmental risk factor – arsenic in drinking water – and cardiac pathology. Can this work be translated on a larger scale to inspire everyday interventions to mitigate adverse environmental effects on human heart health? To find out, listen now.

 

Raihan Kabir, Prithvi Sinha, Sumita Mishra, Obialunanma V. Ebenebe, Nicole Taube, Chistian U. Oeing, Gizem Keceli, Rui Chen, Nazareno Paolocci, Ana Rule, Mark J. Kohr Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart Am J Physiol Heart Circ Physiol, published March 24, 2021. DOI: 10.1152/ajpheart.00435.2020