Medical Physiology Commons^™

Angiotensin Ii-Induced Hypertension Is Attenuated By Overexpressing Copper/Zinc Superoxide Dismutase In The Brain Organum Vasculosum Of The Lamina Terminalis., John P. Collister, Heather Taylor-Smith, Donna Drebes, David Nahey, Jun Tian, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Angiotensin II (AngII) can access the brain via circumventricular organs (CVOs), including the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), to modulate blood pressure. Previous studies have demonstrated a role for both the SFO and OVLT in the hypertensive response to chronic AngII, yet it is unclear which intracellular signaling pathways are involved in this response. Overexpression of copper/zinc superoxide dismutase (CuZnSOD) in the SFO has been shown to attenuate the chronic hypertensive effects of AngII. Presently, we tested the hypothesis that elevated levels of superoxide (O2 (∙-)) in the OVLT contribute to the hypertensive effects …

Determining The Effect Of Knocking Out Microrna-21 On Subsarcolemmal And Interfibrillar Mitochondria, Madhur Batra

Theses and Dissertations

Type 2 diabetes mellitus is a growing problem across the world and has significant pathological changes associated with it, including diabetic cardiomyopathy, wherein cardiac function is reduced. MicroRNA-21 has been shown to play a role in both the heart and diabetes so it was thought that knocking out miR-21 could have a protective effect on oxidative phosphorylation function in diabetic mice. Subsarcolemmal and interfibrillar mitochondria were isolated from adult male WT, miR-21 KO, db/db, and double knockout mice (db/db and miR-21 KO cross) and evaluated for function. Knocking out miR-21 in diabetic mice showed a restorative effect in Complex I …

Interaction Between Angiotensin Ii And Bdnf In Modulating Sympathetic Nerve Activity, Bryan K. Becker

Theses & Dissertations

Over activation of the sympathetic nervous system is prevalent in many forms of cardiovascular disease such as chronic heart failure (CHF) and hypertension. Although increased neuronal renin-angiotensin system activity in presympathetic neurons has been well implicated in mediating this sympatho-excitation, many of the neuronal effects of angiotensin II (Ang II) signaling remain poorly understood. One particular mechanism of Ang II-mediated increases in presympathetic neuronal activity is through reductions in voltage-gated K⁺ currents. Another pathway that has profound effects on neuronal K⁺ currents and that has been previously implicated in Ang II-signaling is brain-derived neurotrophic factor (BDNF) activity through …

Hiv-1-Tat Protein Inhibits Sc35-Mediated Tau Exon 10 Inclusion Through Up-Regulation Of Dyrk1a Kinase, Ferdous Kadri, Marco Pacifici, Anna Wilk, Amanda Parker-Struckhoff, Luis Del Valle, Kurt F. Hauser, Pamela E. Knapp, Christopher Parsons, Duane Jeansonne, Adam Lassak, Francesca Peruzzi

School of Medicine Faculty Publications

The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism …

Bdnf Contributes To Angiotensin Ii-Mediated Reductions In Peak Voltage-Gated K+ Current In Cultured Cath.A Cells., Bryan K. Becker, Han-Jun Wang, Changhai Tian, Irving H. Zucker

Journal Articles: Cellular & Integrative Physiology

Increased central angiotensin II (Ang II) levels contribute to sympathoexcitation in cardiovascular disease states such as chronic heart failure and hypertension. One mechanism by which Ang II increases neuronal excitability is through a decrease in voltage-gated, rapidly inactivating K(+) current (IA); however, little is known about how Ang II signaling results in reduced IA. Brain-derived neurotrophic factor (BDNF) has also been demonstrated to decrease IA and has signaling components common to Ang II. Therefore, we hypothesized that Ang II-mediated suppression of voltage-gated K(+) currents is due, in part, to BDNF signaling. Differentiated CATH.a, catecholaminergic cell line treated with BDNF for …

Diabetic Ketoacidosis: Pathophysiology And Treatment, Laura E. Mumme

The Kabod

The pathophysiology of DKA in patients with T1D is addressed, followed by a discussion of proper emergency treatment for this life-threatening condition.

Relevance Of The Carotid Body Chemoreflex In The Progression Of Heart Failure., David C. Andrade, Claudia Lucero, Camilo Toledo, Carlos Madrid, Noah J. Marcus, Harold D. Schultz, Rodrigo Del Rio

Journal Articles: Cellular & Integrative Physiology

Chronic heart failure (CHF) is a global health problem affecting millions of people. Autonomic dysfunction and disordered breathing patterns are commonly observed in patients with CHF, and both are strongly related to poor prognosis and high mortality risk. Tonic activation of carotid body (CB) chemoreceptors contributes to sympathoexcitation and disordered breathing patterns in experimental models of CHF. Recent studies show that ablation of the CB chemoreceptors improves autonomic function and breathing control in CHF and improves survival. These exciting findings indicate that alterations in CB function are critical to the progression of CHF. Therefore, better understanding of the physiology of …

Characterization Of The Nicotine-Induced Endoplasmic Reticulum Stress Response In The Rat Placenta In Vivo And In Vitro, Michael Ka Chun Wong

Electronic Thesis and Dissertation Repository

Nicotine exposure during pregnancy leads to adverse health outcomes, including compromised placental development. Although the molecular mechanisms remain elusive, recent studies identified that endoplasmic reticulum (ER) stress may underlie poor placentation. Therefore, we were interested in investigating the effects of nicotine exposure on the ER stress response in the placenta. A well-established maternal nicotine exposure rat model and Rcho-1 trophoblast giant cell model were utilized to address the research questions. Maternal nicotine exposure in vivo led to elevated ER stress in association with impaired disulfide bond formation and hypoxia. Nicotine exposure in vitro further differentiated that ER stress may be …

Standardization Of The Experimental Autoimmune Myasthenia Gravis (Eamg) Model By Immunization Of Rats With Torpedo Californica Acetylcholine Receptors- Recommendations For Methods And Experimental Designs., Mario Losen, Pilar Martinez-Martinez, Peter C. Molenaar, Konstantinos Lazaridis, Socrates Tzartos, Talma Brenner, Rui-Sheng Duan, Jie Luo, Jon Lindstrom, Linda Kusner

Pharmacology and Physiology Faculty Publications

Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR) is characterized by a chronic, fatigable weakness of voluntary muscles. The production of autoantibodies involves the dysregulation of T cells which provide the environment for the development of autoreactive B cells. The symptoms are caused by destruction of the postsynaptic membrane and degradation of the AChR by IgG autoantibodies, predominantly of the G1 and G3 subclasses. Active immunization of animals with AChR from mammalian muscles, AChR from Torpedo or Electrophorus electric organs, and recombinant or synthetic AChR fragments generates a chronic model of MG, termed experimental autoimmune myasthenia gravis (EAMG). …

Effects Of Uremic Serum On Isolated Cardiac Myocyte Calcium Cycling And Contractile Function, Sankaridrug Periyasamy, Jie Chen, Derek Cooney, Patricia Carter, Eiad Omran, Jiang Tian, Snigdha Priyadarshi, Alexei Bagrov, Olga Fedorova, Deepak Malhotra, Zijian Xie, Joseph Shapiro

Zijian Xie

Background: Diastolic dysfunction occurs in patients with chronic renal failure. Moreover, serum from uremic patients contains one or more inhibitors of the plasmalemmal Na,K-ATPase (sodium pump). We hypothesized that a circulating substance present in uremic sera contributes to both sodium pump inhibition and diastolic dysfunction.

Methods: Serum samples were obtained from six patients with chronic renal failure and diastolic dysfunction.

Results: Their serum samples caused marked inhibition of Na,K-ATPase purified from dog kidney at all concentrations studied (all P < 0.01) and also impaired ouabain-sensitive rubidium uptake by myocytes isolated from Sprague-Dawley rats (P < 0.01). These cardiac myocytes were studied for their contractile function with video-edge detection and calcium metabolism with indo-1 fluorescence spectroscopy after exposure to these uremic sera. These uremic sera caused increases in myocyte fractional shortening (P < 0.01) as well as an increase in the time constant of relengthening (P < 0.01). Examining the calcium transient, the time constant for calcium recovery was also increased (P < 0.01). Exposure of these cells to sera from age- and sex-matched healthy subjects did not result in significant changes in contraction or calcium cycling. Extracts of uremic serum samples inhibited isolated Na,K-ATPase whereas extracts of normal serum samples did not. The effect of uremic serum extracts on contractile function and calcium cycling were quite similar to that of intact serum or the addition of ouabain. Co-incubation of uremic serum extract with an antibody fragment directed against digoxin markedly attenuated the inhibition of Na,K-ATPase activity and completely prevented any effects on calcium cycling or contractile function.

Conclusion: These data show that one or more substances are present in uremic sera that acutely cause increased force of contraction …

Cardiac Performance In Inbred Rat Genetic Models Of Low And High Running Capacity, J. Chen, G. Feller, J. Barbato, S. Periyasamy, Zijian Xie, L. Koch, Joseph Shapiro, S. Britton

Zijian Xie

Previous work demonstrating that DA inbred rats are superior to COP inbred rats in aerobic treadmill running capacity has indicated their utility as genetic models to explore this trait. We tested the general hypothesis that intermediate phenotypes of cardiac function and calcium metabolism are responsible for the difference in capacity between these strains.

Logical cardiac trait differences were estimated at a tissue (isolated papillary muscle), cellular (isolated left ventricular cells), and biochemical level of organization.

DA hearts were found to give significantly higher values than COP hearts for: (1) maximal developed tension (38.3 % greater), and rates of tension change …

Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity In The ∆7 Sma Mouse, Vicki L. Mcgovern, Aurelie Massoni-Laporte, Xueyong Wang, Thanh T. Le, Hao T. Le, Mark M. Rich, Arthur H. M. Burghes

Neuroscience, Cell Biology & Physiology Faculty Publications

Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. TheSMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However theSMN2 gene does produce some full-length SMN and theSMN2 copy number along with how …

Higher Hepatic Mir-29 Expression In Undernourished Male Rats During The Postnatal Period Targets The Long-Term Repression Of Insulin-Like Growth Factor 1, Gurjeev Sohi, Andrew Revesz, Julie Ramkumar, Daniel B. Hardy

Physiology and Pharmacology Publications

A nutritional mismatch in postnatal life of low birth weight offspring increases the risk of developing the metabolic syndrome. Moreover, this is associated with decreased hepatic insulin-like growth factor 1 (Igf1) expression, leading to impaired growth and metabolism. Previously we have demonstrated that the timing of nutritional restoration in perinatal life can differentially programhepatic gene expression. While micro RNAs also play an important role in silencing gene expression, to date, the impact of a nutritional mismatch in neonatal life on their long-term expression has not been evaluated. Given the complementarity of miR-29 to the 3i-UTR of Igf1, we examined how …

Editorial: Carotid Body: A New Target For Rescuing Neural Control Of Cardiorespiratory Balance In Disease., Rodrigo Del Rio, Rodrigo Iturriaga, Harold D. Schultz

Journal Articles: Cellular & Integrative Physiology

No abstract provided.

Inhibition Of Elongation Factor 1a-1 Activity And Hepatic Lipotoxicity, Alexandra Margaret Anne Hetherington

Electronic Thesis and Dissertation Repository

Elongation factor 1A-1 (eEF1A-1) was previously identified as a mediator of fatty acid-induced cell death (lipotoxicity) downstream of endoplasmic reticulum (ER) stress. Furthermore, inhibition of the peptide elongation activity of eEF1A-1 with the cyclic depsipeptide didemnin B (DB) diminishes ER stress and lipotoxicity in cultured hepatocytes. Since ER stress is involved in nonalcoholic fatty liver disease (NAFLD), it was hypothesized that administration of DB to obese mice with NAFLD would reduce hepatic lipotoxicity. Treatment with DB for one week improved several parameters associated with hepatic lipotoxicity and modestly decreased food intake without evidence of illness. Liver triglycerides and protein markers …

Kiss1r Signaling Promotes Breast Cancer Drug Resistance, Alexandra J. Blake

Electronic Thesis and Dissertation Repository

Kisspeptins signal via the G-protein coupled receptor, KISS1R, and act as metastasis suppressors in numerous cancers. In estrogen receptor (ERα)-negative breast cancer cells, however, KISS1R signaling promotes cell invasion by activating the epidermal growth factor receptor (EGFR). Unfortunately, clinical success of anti-EGFR therapeutics has been limited, as patients often develop drug resistance. Recently, another receptor tyrosine kinase, AXL, has been shown to promote breast cancer drug resistance. We hypothesize that KISS1R promotes EGFR expression and induces breast cancer drug resistance. We demonstrated that KISS1R increases EGFR transcription, by increasing SP-1 binding to the EGFR promoter, as demonstrated by chromatin immunoprecipitation …

Identifying The Molecular Mechanisms Of Early Cachexia Using Whole Transcriptome Sequencing In Muscle And Fat Biopsies From Cancer Patients, Amal Hussain Al Hadad

Dissertations

Cancer cachexia is responsible for one third of cancer–related deaths and contributes to the death of many others. More than 80% of cancer patients are cachectic towards the end of life. Despite intensive research, the mechanisms of cancer cachexia are still poorly understood. It is our hypothesis that identification of early changes in gene expression in cachexia will lead to an improved understanding of the mechanism that trigger this important problem in cancer patients. Thus, to shed light on the mechanisms involved in the major cachexia target tissues, we investigated the entire transcriptome in muscle and fat to identify altered …

Long-Term Hypoxia Alters Ovine Fetal Adrenal Enos And Cortisol Biosynthesis, Elizabeth Anne Newby

Loma Linda University Electronic Theses, Dissertations & Projects

Maintaining normal levels of cortisol in response to chronic stress, while retaining the ability to respond to acute stress, is important for ensuring normal fetal growth and development. Long-term hypoxia (LTH) causes adaptations in the fetal hypothalamopituitary- adrenal (HPA) axis that maintain basal cortisol levels but enhance production in response to a secondary stress. Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS) in the adrenal cortex, plays a significant role in regulating cortisol production in the LTH fetus. The production of NO is regulated by eNOS activity which can be altered via phosphorylation through key signaling pathways. In …

Lipid Regulation As A Critical Factor In The Development Of Alzheimer's Disease, Michael A. Castello

Loma Linda University Electronic Theses, Dissertations & Projects

Alzheimer’s disease (AD) is the most common form of dementia in the United States, representing around eighty percent of all cases. For more than two decades, researchers have been led by the amyloid cascade hypothesis, which assumes that accumulation of the amyloid peptide Aβ, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in AD. To date, therapies have largely focused on removing Aβ from the brain, an approach that has produced disappointing clinical outcomes. I present an alternative hypothesis in which Aβ production and aggregation is a symptom of a larger, systemic disease …

Coaching And Concussions: Prevention, Education, And Perspective, Colby J. Felts

Honors Thesis

The large participation of players and coaches in football has made it one of the most popular sports in America. Concussions have specifically gained national attention in football due to frequent, high impact collisions. A concussion injury poses a unique threat in high school football because of the developing adolescent brain and high participation numbers. Additionally, lack of medical personnel to diagnose concussions at the high school level imposes a legal duty on the coaches. The thesis develops a recommended plan of action for directors of Iowa high school football to assist in preserving the future of the sport. A …