Exploring therapeutic approaches for Marfan syndrome associated aortic aneurysm

Esfandiearei will be discussing her research on understanding the underlying mechanisms contributing to the progression of aortic aneurysm in Marfan syndrome and the protective effects that exercise may have on the disease process in both laboratory animal models and human patients. Her research has been supported by the Canadian Institutes of Health Research (CIHR), Rare Diseases Foundation, and the Marfan Foundation

Endothelin-Induced Sarcoplasmic Reticulum Calcium Depletion Waves in Vascular Smooth Muscle Cells

Agonist-stimulated waves of elevated cytoplasmic Ca2+ concentration ([Ca2+]i ) regulate blood vessel tone and vasomotion in vascular smooth muscle. Previous studies employing cytoplasmic Ca2+ indicators revealed that these Ca2+ waves were generated by a combination of inositol 1,4,5-trisphosphate (IP3) and Ca2+ induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR); although, some of the mechanistic details remain uncertain. However, these findings were derived indirectly from observing agonist-induced [Ca2+]i fluctuations in the cytoplasm.
Here, for the first time, we have recorded Endothelin-1 (ET-1) induced waves of Ca2+ depletion from the SR lumen in vascular smooth muscle cells (VSMCs) using a calsequestrin-targeted Ca2+ indicator. Our findings show that these waves: (1) are due to regenerative CICR by the receptors for IP3 (IP3R), (2) have a marked latency period, (3) are characterized by a transient increase in SR Ca2+ ([Ca2+]SR ) both at the point of origin and at the wave front, (4) proceed with diminishing velocity, and (5) are arrested by the nuclear envelope. Our quantitative model indicates that the gradual decrease in the velocity of the SR depletion wave, in the absence of external Ca2+, results from continuity of the SR luminal network

Targeting enteroviral 2A protease by a 16-mer synthetic peptide: Inhibition of 2Apro-induced apoptosis in a stable Tet-on HeLa cell line

AbstractEnteroviridae such as coxsackievirus are important infectious agents causing viral heart diseases. Viral protease 2A (2Apro) initiates the virus life cycle, and is an excellent target for developing antiviral drugs. Here, to evaluate the validity of the 2Apro as a proper therapeutic target, and based on the existing information and molecular dynamics, a 16-mer peptide was designed to specifically target the active site of protease 2Apro in order to block the activity of CVB3 2Apro. We showed that the peptide could compete with endogenous substrate in a concentration-dependent manner. Further, we established a HeLa cell line that expressed 2Apro. Expression of 2Apro resulted in significant morphological alteration and eventual cell death. Western blot and viability assay showed that the 16-mer peptide (200 μg/ml) could significantly block 2Apro activity and its cytotoxic effect. Future modification of the 16-mer peptide can improve its affinity for 2Apro and therefore develop effective antiviral drug

Exploring therapeutic approaches for Marfan syndrome associated aortic aneurysm

Esfandiearei will be discussing her research on understanding the underlying mechanisms contributing to the progression of aortic aneurysm in Marfan syndrome and the protective effects that exercise may have on the disease process in both laboratory animal models and human patients. Her research has been supported by the Canadian Institutes of Health Research (CIHR), Rare Diseases Foundation, and the Marfan Foundation

The role of protein kinase B/Akt in pathogenesis of coxsackievirus B3 myocarditis

Viral myocarditis is a major cause of sudden cardiac death in children and young adults. Among viruses, coxsackievirus B3 (CVB3), a small non-enveloped single-stranded RNA enterovirus in the Picornaviridae family, is the most prominent infective agent for myocarditis, causing myocardial injury that, at times leads to end-stage dilated cardiomyopathy. Recently, more consideration has been devoted to the role of signalling pathways in the pathogenesis of enteroviral myocarditis as a route for identifying new potential therapeutic targets. The role of signalling proteins including the extracellular signal-regulated kinase (ERKI/2 MAPK), stress-activated protein kinase c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) during CVB3 infection has been comprehensively studied by us and others. However, the potential regulatory function of other kinases such as the survival signalling molecule protein kinase B/Akt remains elusive. In the present study, we have investigated the potential regulatory function of the PI3K/Akt pathway in progression of CVB3-induced myocarditis. Our findings demonstrate that CVB3 enhances Akt phosphorylation through a phosphatidylinositol-3 kinase (PI3K)-dependent mechanism. Inhibition of Akt significantly suppresses viral RNA expression and progeny release while increasing apoptosis of infected cells. Interestingly, inhibition of apoptotic events does not reverse the inhibitory effect of Akt inhibition on virus life replication, suggesting that the observed regulatory role of Akt is not dependent on the anti-apoptotic function of this protein kinase. Virus-induced Akt phosphorylation in mouse cardiomyocytes and HeLa cells is also mediated through the integrin-linked kinase (ILK). Inhibition of ILK significantly reduces viral replication and progeny release and improves viability of infected cardiomyocytes. Over-expression of a constitutively active form of Akt protein within virus-infected cells has provided evidence that the protective effect of ILK inhibition is dependent on associated down-regulation of virus-induced Akt activation. In the present study, we also investigated the role of the transcription factor nuclear factor kappa-B (NFkB) as a candidate downstream mediator of signals through the PI3K/Akt cascade in regulating CVB3 replication and virus-mediated cytopathic effects. Our findings suggest that activation of NFkB is an early event with an anti-apoptotic function. Inhibition of PI3K and Erk1/2 pathways significantly blocks virus-induced NFkB activation, proposing a major role for these kinases in regulation of host transcriptional events during CVB3 infection. Most importantly, short-term treatment of infected cells with tumor necrosis factor-α [i.e. tumour necrosis factor-α] (TNF-α), a potent activator of NFkB, rescues infected cells, apparently through increasing the DNA-binding activity of NFkB. Long-term treatment with TNF-α, however, has been shown to be detrimental to the host cell, emphasizing the importance of the delicate balance between deleterious and protective effects of NFkB activation. In summary, this dissertation presents the first report on the regulatory role of the PI3K/Akt pathway during the course of enteroviral infection, provides valuable information on molecular mechanisms underlying CVB3 pathogenesis, and offers new insights to our effort in establishing an effective therapeutic approach to alleviate enteroviral myocarditis.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Shifts in Rat Aortic and Mesenteric Endothelial Responses to Streptozotocin-Induced Diabetes with Respect to Sex: the Role of EDRFs and Superoxide

Diabetes affects male and female vascular beds differently. However, the mechanisms underlying the interaction of sex and diabetes remain to be investigated

Integrin-linked kinase functions as a downstream signal of platelet-derived growth factor to regulate actin polymerization and vascular smooth muscle cell migration

Background: Vascular smooth muscle cell migration and accumulation in response to growth factors extensively contribute to the development of intimal thickening within the vessel wall. Cumulative evidence has shown that actin cytoskeleton polymerization and rearrangement are critical steps during cellular spreading and migration. Integrin-linked kinase, an intracellular serine/threonine kinase, is a cytoplasmic interactor of integrin beta-1 and beta-3 receptors regulating cell-cell and/or cell-extracellular matrix interaction, cell contraction, extracellular matrix modification, and cell spreading and migration in response to various stimuli. However, the regulatory role of ILK during vascular smooth muscle cell migration and the importance of integrin signaling in occlusive vascular diseases are not yet fully elucidated. Results In the present study, we report that integrin-linked kinase controls mouse aortic smooth muscle cell migration in response to platelet-derived growth factor. We have also identified p38 mitogen activated protein kinase as a downstream signaling pathway of the integrin-linked kinase that regulates platelet-derived growth factor-induced actin polymerization and smooth muscle cell migration. Conclusion This study will provide new insights into the potential therapeutic value of modulating integrin signaling in an attempt to block or delay smooth muscle cell migration and the progression of vascular diseases.Anesthesiology, Pharmacology and Therapeutics, Department ofMedicine, Faculty ofReviewedFacult

Impact of maternal dietary folic acid or choline dietary deficiencies on vascular function in young and middle-aged female mouse offspring after ischemic stroke

Adequate maternal dietary levels of one-carbon metabolites, such as folic acid and choline, play an important role in the closure of the neural tube in utero; however, the impact of deficiencies in one-carbon (1C) metabolism on offspring neurological function after birth remain undefined. Stroke is one of the leading causes of death and disability globally. The aim of our study was to determine the impact of maternal 1C nutritional deficiencies on cerebral and peripheral blood flow after ischemic stroke in adult female offspring. In this study, female mice were placed on either control (CD)-, folic acid (FADD)-, or choline (ChDD)-deficient diets before pregnancy. Female offspring were weaned onto a CD for the duration of the study. Ischemic stroke was induced in offspring and after 6 wk cerebral and peripheral blood flow velocity was measured using ultrasound imaging. Our data showed that 11.5-mo-old female offspring from ChDD mothers had reduced blood flow in the posterior cerebral artery compared with controls. In peripheral blood flow velocity measurements, we report an aging effect. These results emphasize the importance of maternal 1C diet in early life neuro-programming on long-term vasculature health.NEW & NOTEWORTHY We demonstrate that a maternal dietary deficiency in one-carbon (1C) metabolites result in reduced cerebral blood flow in adult female offspring after ischemic stroke, but the long-term effects are not present. This result points to the key role of the maternal diet in early life neuroprogramming, while emphasizing its effects on both fetal development and long-term cerebrovascular health.12 month embargo; first published 06 October 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]