Publications by authors named "Timothy D Bryson"

8 Publications

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Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest.

Mol Neurobiol 2022 Jan 14. Epub 2022 Jan 14.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO administrated during CPR could achieve therapeutic serum magnesium levels within 15 min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107 mg/kg, 215 mg/kg, or 430 mg/kg MgSO IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15 min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO during CPR had no effect on ROSC rate (p > 0.05). IM MgSO treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO during CPR achieves up to fourfold baseline serum magnesium levels within 15 min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.
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http://dx.doi.org/10.1007/s12035-021-02645-xDOI Listing
January 2022

Prostaglandin E2 EP receptors in cardiovascular disease: An update.

Biochem Pharmacol 2022 01 22;195:114858. Epub 2021 Nov 22.

Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States. Electronic address:

This review article provides an update for the role of prostaglandin E2 receptors (EP1, EP2, EP3 and EP4) in cardiovascular disease. Where possible we have reported citations from the last decade although this was not possible for all of the topics covered due to the paucity of publications. The authors have attempted to cover the subjects of ischemia-reperfusion injury, arrhythmias, hypertension, novel protein binding partners of the EP receptors and their pathophysiological significance, and cardiac regeneration. These latter two topics bring studies of the EP receptors into new and exciting areas of research that are just beginning to be explored. Where there is peer-reviewed literature, the authors have placed particular emphasis on clinical studies although these are limited in number.
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http://dx.doi.org/10.1016/j.bcp.2021.114858DOI Listing
January 2022

Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction.

Circ Genom Precis Med 2021 06 17;14(3):e003140. Epub 2021 May 17.

Center for Individualized and Genomic Medicine Research (CIGMA) (H.G., J. Luzum, T.D.B., K.W., D.E.L.), Henry Ford Hospital.

Background: It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS).

Methods: Patients meeting Framingham criteria for HF with EF<50% were enrolled (N=1017) and plasma underwent SOMAscan profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and NT-proBNP (N-terminal pro-B-type natriuretic peptide), then was tested in the validation cohort. Risk stratification improvement was evaluated by C statistic, integrated discrimination index, continuous net reclassification index, and median improvement in risk score for 1-year and 3-year mortality.

Results: Participants' mean age was 68 years, 48% identified as Black, 35% were female, and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio, 2.27 [95% CI, 1.84-2.82], =6.3×10), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (=2.2×10), and it remained significant after adjustment for clinical score and NT-proBNP (hazard ratio, 1.37 [95% CI, 1.05-1.79], =0.021). The HFrEF-PRS improved metrics of risk stratification (C statistic change, 0.009, =0.612; integrated discrimination index, 0.041, =0.010; net reclassification index=0.391, =0.078; median improvement in risk score=0.039, =0.016) and associated with cardiovascular death and HF phenotypes (eg, 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF.

Conclusions: A plasma multiprotein score improved risk stratification in patients with HFrEF and identified novel candidates.
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http://dx.doi.org/10.1161/CIRCGEN.120.003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221080PMC
June 2021

Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons.

Cell Death Dis 2021 05 12;12(5):475. Epub 2021 May 12.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Mitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.
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http://dx.doi.org/10.1038/s41419-021-03752-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115279PMC
May 2021

Machine learning-based classification of mitochondrial morphology in primary neurons and brain.

Sci Rep 2021 03 4;11(1):5133. Epub 2021 Mar 4.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

The mitochondrial network continually undergoes events of fission and fusion. Under physiologic conditions, the network is in equilibrium and is characterized by the presence of both elongated and punctate mitochondria. However, this balanced, homeostatic mitochondrial profile can change morphologic distribution in response to various stressors. Therefore, it is imperative to develop a method that robustly measures mitochondrial morphology with high accuracy. Here, we developed a semi-automated image analysis pipeline for the quantitation of mitochondrial morphology for both in vitro and in vivo applications. The image analysis pipeline was generated and validated utilizing images of primary cortical neurons from transgenic mice, allowing genetic ablation of key components of mitochondrial dynamics. This analysis pipeline was further extended to evaluate mitochondrial morphology in vivo through immunolabeling of brain sections as well as serial block-face scanning electron microscopy. These data demonstrate a highly specific and sensitive method that accurately classifies distinct physiological and pathological mitochondrial morphologies. Furthermore, this workflow employs the use of readily available, free open-source software designed for high throughput image processing, segmentation, and analysis that is customizable to various biological models.
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http://dx.doi.org/10.1038/s41598-021-84528-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933342PMC
March 2021

The deleterious role of the prostaglandin E EP receptor in angiotensin II hypertension.

Am J Physiol Heart Circ Physiol 2020 04 6;318(4):H867-H882. Epub 2020 Mar 6.

Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan.

Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E (PGE) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP and EP receptors is a major determinant of end-organ damage in the diseased heart. Thus EP is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP receptor is protective in an ANG II hypertension (HTN) model. To test our hypothesis, male 10- to 12-wk-old C57BL/6 mice were anesthetized with isoflurane and osmotic minipumps containing ANG II were implanted subcutaneously for 2 wk. We found that antagonism of the EP receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP-transgenic mice, which overexpress EP in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN. This study is the first to show that systemic treatment with an EP receptor antagonist (L798,106) attenuates the angiotensin II-induced increase in blood pressure in mice. The results from this project could complement existing hypertension therapies by combining blockade of the EP receptor with antihypertensive drugs.
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http://dx.doi.org/10.1152/ajpheart.00538.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191497PMC
April 2020

Prostaglandin E and an EP4 receptor agonist inhibit LPS-Induced monocyte chemotactic protein 5 production and secretion in mouse cardiac fibroblasts via Akt and NF-κB signaling.

Prostaglandins Other Lipid Mediat 2019 10 20;144:106349. Epub 2019 Jun 20.

Hypertension & Vascular Research Division, Dept. Internal Medicine, USA; Dept. of Physiology, Wayne State University School of Medicine, USA. Electronic address:

Background: Prostaglandin E2 (PGE) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We have previously reported that mice lacking the EP4 receptor in the cardiomyocytes develop heart failure with a phenotype of dilated cardiomyopathy. Also, these mice have increased levels of chemokines, like MCP-5, in their left ventricles. We have recently reported that overexpression of the EP4 receptor could improve cardiac function in the myocardial infarction model. Furthermore, we showed that overexpression of EP4 had an anti-inflammatory effect in the whole left ventricle. It has also been shown that PGE can antagonize lipopolysaccharide-induced secretion of chemokines/cytokines in various cell types. We therefore hypothesized that PGE inhibits lipopolysaccharide (LPS)-induced MCP-5 secretion in adult mouse cardiac fibroblasts via its EP4 receptor.

Methods And Results: Our hypothesis was tested using isolated mouse adult ventricular fibroblasts (AVF) treated with LPS. Pre-treatment of the cells with PGE and the EP4 agonist CAY10598 resulted in reductions of the pro-inflammatory response induced by LPS. Specifically, we observed reductions in MCP-5 secretion. Western blot analysis showed reductions in phosphorylated Akt and IκBα indicating reduced NF-κB activation. The anti-inflammatory effects of PGE and EP4 agonist signaling appeared to be independent of cAMP, p-44/42, or p38 pathways.

Conclusion: Exogenous treatment of PGE and the EP4 receptor agonist blocked the pro-inflammatory actions of LPS. Mechanistically, this was mediated via reduced Akt phosphorylation and inhibition of NF-κB.
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http://dx.doi.org/10.1016/j.prostaglandins.2019.106349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778017PMC
October 2019

Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction.

J Mol Cell Cardiol 2018 05 6;118:1-12. Epub 2018 Mar 6.

Hypertension & Vascular Research Division, Dept. of Internal Medicine, USA; Dept. of Physiology, Wayne State University School of Medicine, USA. Electronic address:

Background: Prostaglandin E2 (PGE) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We recently reported that PGE via its EP3 receptor could reduce cardiac contractility of isolated myocytes and the working heart preparation. We thus hypothesized that there is an imbalance in the EP3/EP4 ratio towards EP3 in the failing heart and that overexpression of EP4 in a mouse model of heart failure would improve cardiac function.

Methods And Results: Our hypothesis was tested in a mouse model of myocardial infarction (MI) with the use of AAV9-EP4 driven by the myosin heavy chain promoter to overexpress EP4 in the cardiac myocytes. Echocardiography was performed to assess cardiac function. We found that overexpression of EP4 improved shortening fraction (p = 0.0025), ejection fraction (p = 0.0003), and reduced left ventricular dimension at systole (p = 0.0013). Overexpression of EP4 also significantly reduced indices of cardiac hypertrophy and interstitial collagen fraction. Animals treated with AAV9-EP4 also had a significant decrease in TNFα mRNA expression and in the number of macrophages and T cells migrated post MI coupled with a reduction in the expression of iNOS.

Conclusion: Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production.
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http://dx.doi.org/10.1016/j.yjmcc.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940572PMC
May 2018
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