Progress 08/01/05 to 07/31/11
Outputs
OUTPUTS: Over the last 5 yrs of support for this grant our effort has been directed towards understanding the role played by pro-inflammatory cytokines (PIC), specifically tumor necrosis factor alpha (TNF-a),on neurohumoral exciation in heart failure (HF). We demonstrated that HF increased PIC levels in the paraventricular nucleus (PVN) of the hypothalamus and that blockade of TNF-a in the brain attenuated sympathoexcitation in HF. We then showed that TNF-α interacts with angiotensin receptor (AT-1R)in the PVN & contributes to sympathoexcitation in HF. Since angiotensin (ANG II) & TNF-a are increased in the PVN & induce oxidative stress in HF, we examined the effect of blocking oxidative stress in the brains of HF rats. We showed that blocking oxidative stress decreased PIC and AT-1R activation & prevented the depletion of neuronal nitric oxide in the PVN & that this was accompanied by a decrease in sympathetic nerve activity. We then examined nuclear transcription factor kappa B (NFκB), a critical transcription factor that regulates both PIC & oxidative stress. We showed that NFkB is activated in the PVN after HF & that blockade of NFkB attenuated oxidative stress & AT-1R in the PVN & decreased sympathoexcitation. Furthermore, we demonstrated that TNF-a modulates excitatory & inhibitory neurotransmitters in the PVN & contributes to sympathoexcitation in HF. In addition, we showed similar changes in PIC and NFkB in the PVN of ANGII induced hypertensive animals. These experiments indicate that PIC activation within the PVN mediates the exaggerated sympathetic nerve activity in HF. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Over the past 5 years of support, we have clearly demonstrated a role for brain cytokines and its transcription factor NFkB in inducing oxidative stress and sympathoexcitation in heart failure and hypertension. We have also started exploring the potential signalling molecule in the brain specifically within the paraventricular nucleus on sympathoexcitation in heartfailure. We have identified a unique molecule that alter both pro and anti-inflammatory molecule within the PVN and its possible role on sympathoexcitation. One signaling molecule that has recently gained significant importance because of its novel role in inflammation is glycogen synthase kinase 3b (GSK3b). Our preliminary data indicates that pGSK3b is increased in the PVN of HF rats. Findings from our lab indicate that PIC and NFkB are increased in the PVN and induce superoxide production, therefore it is plausible to suggest that pGSK3β in the PVN might be a crucial signaling molecule regulating the balance between PIC and AIC in the PVN contributing to sympathoexcitation in HF. In addition, we have started to explore non pharmacological mechanisms to attenuate inflammatory molecules and we have demonstrated that moderate intensity exercise training (ExT) decreases myocardial cytokines and attenuates blood pressure in spontaneously hypertensive rats. Our preliminary data also suggest that ExT might be a therapeutic modality to decrease oxidative stress in the brain and attenuate phosphorylation of GSK3 in the PVN and restore the balance between PIC and AIC in the PVN of HF rats.
Publications
- Anuradha Guggilam, Masudul Haque, Edmund Kenneth Kerut, Elizabeth McIIwain, Pamela Lucchesi, Inder Seghal and Francis J. TNF-alpha blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats. Am J Physiol Heart Circ Physiol. 293:H599-609, 2007. (PMID: 17416605)
- Nithya Mariappan, Rajesekaran Soorapan, Masudul Haque, Srinivas Sriramula, J. Francis. TNF-alpha induced mitochondrial oxidative stress and cardiac dysfunction: Restoration by superoxide dismutase mimetic tempol. Am J Physiol Heart Circ Physiol 293: H2726-H2737, 2007. (PMID: 17675574)
- Yu-Ming Kang, Ying Ma, Carrie Elks, Jin-Ping Zheng, Zhi-Ming Yang, and Francis J. Cross talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-κB. Cardiovasc Res. 2008 Sep 1;79(4):671-8 (PMID: 18469338)
- Carrie M. Elks, Nithya Mariappan, Masudul Haque, Anuradha Guggilam,Dewan S.A. Majid and Francis J. Chronic NF-kB blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR rats. Am J Physiol Renal Physiol F298-305, 2009 (PMID: 19073636)
- Nithya Mariappan, Carrie Elks, Bruno Fink and Francis J. TNF-induced mitochondrial damage: a link between mitochondrial complex i activity and left ventricular dysfunction. Free Radical Biology and Medicine. 46(4):462-70, 2009. (PMID: 19041937)
- Kang YM, Ma Y, Zheng JP, Elks C, Sriramula S, Yang ZM, and Francis J. Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovasc Res. 82(3):503-12, 2009 (PMID: 19246475)
- Philip Ebnezer, Nithya Mariappan, Carrie Elks, Masudul Haque and Francis J. Effects of pyrrolidine dithiocarbamate on high-fat diet-induced metabolic and renal alterations in rats. Life Sciences, 85(9-10):357-364, 2009. (PMID: 19631668)
- Mariappan N, Elks CM, Sriramula S, Guggilam A, Liu Z, Borkhsenious O, Francis J. NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res. 2010 Feb 1;85(3):473-83. 3 (PMID- 19729361)
- Deepamala Agarwal, Masudul Haque, Srinivas Sriramula, Nithya Mariappan, Romain Pariaut,and Francis J. Role of Proinflammatory Cytokines and Redox Homeostasis in Exercise-Induced Delayed Progression of Hypertension in Spontaneously Hypertensive Rats. Hypertension, Dec; 54(6):1393-400, 2009. (PMID: 19841289)
- Jeffrey P Cardinale, Srinivas Sriramula, Romain Pariaut, Anuradha Guggilam, Nithya Mariappan,Carrie Elks and Francis J. HDAC Inhibition Attenuates Inflammatory, Hypertrophic and Hypertensive Responses in Spontaneously Hypertensive Rats. Hypertension, 56(3):437-44, 2010 PMID: 20679181
- Carrie Elks and Francis, J. Central adiposity, Systemic Inflammation and the Metabolic Syndrome. Current Hypertension Report, 12(2):99-104, 2010. (PMID: 20424938)
|
Progress 01/01/09 to 12/31/09
Outputs
OUTPUTS: Over the fourth year of this project we have demonstrated that nuclear transcription factor kappa B (NFkB) plays an important role in inducing cytokines in the PVN and contribute to neurohumoral excitation in heart failure and hypertension rats. Blockade of this NFkB with dithiol pyrrolidine thiocarbamate or SN50 which inhibits phosphorylation of IkB attenuate oxidative stress and cytokines in the PVN and left ventricles of heart failure rats. Under the second specific aim we showed that blockade of angiotensin-1 receptor in heart failure or hypertensive rats with losartan attenuated the expression of circulating and tissue levels of cytokines and NFkB in the PVN of heart failure and decreased blood pressure in hypertensive rats. Suggesting a cross talk between the cytokines and renin angiotensin system in heart failure and hypertension. We also demonstrate that myocardial infarction of mice lacking the gene for TNF-α had attenuated oxidative stress and prevented the decrease in neuroonal nitric oxide in the brain when compared to wild type controls. These mice also had decreased levels of circulating norepinephrine levels compared to wild type controls. A manuscript on this subject is under third revision in Hypertension (R3). We have also demonstrated that mice lacking the gene for NFkB (p50) subunit has attenuated sympathoexcitation and proinflammatory cytokines after myocardial infarction. These findings suggests that TNF and its transcriptional factor NFkB in the brain contribute to exaggerated neurohumoral excitation in heart failure. Blocking hypothalamic production of nuclear transcription factor will attenuate brain production of cytokines and might benefit heart failure patients PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
During last year of support from this R01 grant we had published 8 manuscripts and presented 23 abstract at the National meetings. This grant has also resulted in the submission of an R01 grant to understand the role played by transcription factor in the paraventricular nucleus of the brain in inducing hypertension in animals.
Publications
- Yu-Ming Kang, Rong-Li He Li-Min Yang, Da-Nian Qin, Anuradha Guggilam,Carrie Elks, Ning Yan, Zheng Guo, and Joseph Francis. Brain tumor necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovasc Res. 2009 May 20. PMID: 19457890
- Philip Ebnezer, Nithya Mariappan, Carrie Elks, Masudul Haque and Joseph Francis. Diet-induced renal changes in zucker rats are ameliorated by the superoxide dismutase mimetic tempol. Obesity (Silver Spring). 2009 May 7. PMID: 19424163
- Kang YM, Ma Y, Zheng JP, Elks C, Sriramula S, Yang ZM, and Joseph Francis. Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovasc Res. 2009 Jun 1;82(3):503-12 PMC2682616 Available on 2010/06/01
- Carrie M. Elks, Nithya Mariappan, Masudul Haque, Anuradha Guggilam,Dewan S.A. Majid and Joseph Francis. Chronic NF-kB blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR rats. Am J Physiol Renal Physiol F298-305, 2009 PMCID: PMC264386
- Nithya Mariappan, Carrie Elks, Bruno Fink and Joseph Francis. TNF-induced mitochondrial damage: a link between mitochondrial complex I activity and left ventricular dysfunction. Free Radical Biology and Medicine. 46(4):462-70, 2009. PMID: 19041937
- Yu-Ming Kang, Ying Ma, Carrie Elks, Jin-Ping Zheng, Zhi-Ming Yang, and Joseph Francis. Cross talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-κB. Cardiovasc Res. 2008 Sep 1;79(4):671-8 PMID: 18469338
- Srinivas Sriramula,Masudul Haque, Dewan Majid, and Joseph Francis. Involvement of tumor necrosis factor-alpha in Angiotensin II mediated effects on salt intake, blood pressure and cardiac hypertrophy. Hypertension. 2008 May;51(5):1345-51. PMID: 18391105
- Anuradha Guggilam1, Kaushik P Patel3, Masudul Haque1, Philip J Ebenezer1, Daniel R Kapusta2 and Joseph Francis. Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus. Eur J Heart Fail. 2008 Jul;10(7):625-34. PMID: 18550427 PMCID: PMC2593148 [Available on 2009/07/01}
|
Progress 01/01/08 to 12/31/08
Outputs
OUTPUTS: Considerable progress in research has been made by the P.I. over the last year of this RO1 Award. The PI's work has been continuosly being recognized by the AHA and high blood pressure council. As mentioned in the last year progress report we had started working on understanding the role of cytokines in hypertensive response. Under specific aim I we had proposed studies understanding the role of TNF in inducing neurohumoral excitation in rats. Here we demonstrate that mice lacking the gene for TNF-alpha had attenuated oxidative stress and neurohumoral excitation in heart failure. Under specific aim II we proposed to study whether the Central nervous system cytokines activate neurohumoral excitation in heart failure, either directly or via an interaction with products of the intrinsic brain renin-angiotensin system. Under this specific aim we show that central nervous system infusion of cytokine blocker or inhibiting nuclear transcription factor or angiotensin receptor blocker attenuate oxidative stress, proinflammatory cytokines in heart failure rats. These treatments inhibited neurohumoral excitation by decreasing the TNF-alpha, IL-6 and IL-1 beta in the paraventricular nucleus of the heart failure. We also show that nuclear transcription factor might be link in upregulating oxidative stress and PIC in the PVN and contributing neurohumoral excitation in heart failure. PARTICIPANTS: Dr. Joseph Francis, PI Dr. Yu-Ming Kang, Asst Professor Dr. Philip Ebenezer, post-doc Dr. Nithya Mariappan, Post-doc Dr. Masdhul Haque, Post-doc Dr. Srinivas Sriramula, Graduate Student Dr. Anuradha Guggilam,Graduate student Ms. Carrie Elks, graduate student Mr. Jeffrey Cardinale, graduate student TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Over the third year of this project we have demonstrated that nuclear transcription factor kappa B (NFkB) plays an important role in inducing cytokines in the PVN and contribute to neurohumoral excitation in heart failure rats. Blockade of NFkB with dithiol pyrrolidine thiocarbamate attenuate oxidative stress and cytokines in the PVN and left ventricles of heart failure rats. Under the second specific aim we showed that blockade of angiotensin-1 receptor in heart failure rats with losartan attenuated the expression of circulating and tissue levels of cytokines in the PVN of heart failure rats. Suggesting a cross talk between the cytokines and renin angiotensin system in heart failure. We also demonstrate that myocardial infarction of mice lacking the gene for TNF-α had attenuated oxidative stress and increased neuroonal nitric oxide when compared to wild type controls. These mice also had decreased levels of circulating norepinephrine levels compared to wild type controls. These findings suggests that TNF and its transcriptional factor NFkB in the brain contribute to exaggerated neurohumoral excitation in heart failure. Blocking hypothalamic production of cytokines will benefit heart failure patients.
Publications
- Philip J. Ebenezer, Nithya Mariappan,Masudul Haque,Carrie Elks and Joseph Francis. NFkB blockade attenuates oxidative stress and improves metabolic abnormalities in Obese Zucker rats. The FASEB Journal 947.16, 2008.
- CarrieM.Elks, MasudulHaque, NithyaMariappan, Anuradha Guggilam, and Joseph Francis. Long-term cytokine blockade attenuates hypertensive response and protects against renal injury in spontaneously hypertensive rats. The FASEB Journal 969.9, 2008.
- Yu-Ming Kang, Li-Jing Gao, Jing-Hui Lei, Zhi-Ming Yang, Ji-Yuan Lv, Joseph Francis. Renin angiotensin blockade attenuates proinflammatory cytokines activation in the microglia of paraventricular nucleus of heart failure rats The FASEB Journal 952.19, 2008
- Shahid M, Joseph Francis, Dewan S.Majid Renal vasoconstrictor and natriuretic effect of acute administration of human recombinant TNF- (rTNF) in mice The FASEB Journal 923.1, 2008.
- NithyaMariappan, CarrieM.Elks, Kyla Preejan, Srinivas Sriramula and Joseph Francis. Interaction of TNF with ANG II contribute to mitochondrial oxidative stress and end organ damage in rats. The FASEB Journal 923.3, 2008.
- Nithya Mariappan; Carrie Elks; Masudul Haque; Philip J Ebnezer; Elizabeth McIIwain; Edmund K Kerut; Joseph Francis. NFkb Blockade Attenuate Cytokines And Oxidative Stress In The Paraventricular Nucleus And Decreases Neurohumoral Excitation In Spontaneously Hypertensive Rats. Circulation 116:II-283, 2007
|
Progress 01/01/07 to 12/31/07
Outputs
Under specific aim I we had proposed studies understanding whether chronic TNF-α infusion induces neurohumoral excitation in rats. Here we demonstrate that chronic TNF-α induces end organ damage in normal rats by inducing oxidative stress in the mitochondria and tissue of rats. Under specific Aim II: we had proposed studies elucidating the expression of cytokines in the PVN of heart failure rats. Here we demonstrate that myocardial infarction induces a sustained increase in PVN cytokines and depletion of neuronal nitiric oxide and contribute to exaggerated renal sympathetic nerve activity. In this study we also show that brain blockade of angiotensin receptor (losartan) attenuate oxidative stress and cytokines in the PVN of heart failure rats.
Impacts
Conclusion 1: TNF-a induced mitochondrial damage in the heart and kidney could contribute to the pathophysiology of cardiovascular disease. Preventing excessive production of TNF-a might benefit patients with cardiovascular disease. Conclusion 2: These findings suggest the cross talk between the cytokines and renin angiotensin system within the brain contribute to sympatho-excitation in heart failure. In addition we have explored the role played by TNF-α in inducing oxidative stress in the brain and its effect on neurohumoral excitation in heart failure using TNF-α knock-out mice.
Publications
- L.Kopan, A.Castillo, Joseph Francis and D.S.A. Majid. Renal responses to angiotensin II are attenuated in knock-out mice lacking the gene for tumor necrosis factor-alpha. The FASEB Journal 595.20, 2007.
- E. Tobaldini, A.Porta, K.R. Casali, Joseph Francis, S-G. Wei, R.M. Weiss, Z-H. Zhang, R.Felder and N. Montano. Central mineralocorticoid receptor antagonism improves autonomic neural control in heart failure rats. The FASEB Journal 910.4, 2007.
- Jie Liao, Joseph Francis, Robert J Richards, Rubin Zhang, Erwin A. Aguilar and Efrain Reisin. Tesaglitazar, a dual PPARα/γ agonist, improves metabolic abnormalities and attenuate microalbuminuria in Obese Zucker rats. American Society of Nephrology abstract 2006.
- Nithya Mariappan, Srinivas Sriramula, Masudul Haque and Joseph Francis. TNF-α blockade prevents mitochondrial dysfunction in the heart and attenuates hypertensive response in salt sensitive hypertensive rats. Circulation 114(18)1416, 2006.
|
Progress 01/01/06 to 12/31/06
Outputs
Over the first year of this project we have demonstrated that chronic TNF-alpha induces neurohumoral excitation by inducing oxidative stress in the PVN of normal rats. The cytokines levels are increased both in the periphery and in the PVN of heart failure rats. Blockade of cytokines attenuates neurohumoral excitation by decreasing oxidative stress in the PVN of heart failure rats. Finally the cardiac sympathetic afferent activation contributes to increased cytokine production and oxidative stress in the PVN of heart failure rats. These finding suggests that brain production of cytokines plays an important role in neurohumoral exciation in heart failure. Preventing brain produciton of cytokines might benefit heart failure patients. In the second year of this project we will continue to work on each aim proposed in the study. We will employ cytokine knock-out mice (TNF-alpha and IL-6 knock-out mice) in our studies. We will dissect out the individual contributions of
the cytokines in neurohumoral excitation in heart failure. We will initiates study to understand the role of brain cytokines in the progression of heart failure by implanting and infusion drugs into the brain of animals. We will also try to publish some of the completed work during the second year of the project.
Impacts
same as the previous one. NO change in the impact statement.
Publications
- 1. Julie N. Hartfield, Masudul Haque, Dewan S.A. Majid, and Joseph Francis. Angiotensin II induced upregulation of myocardial eNOS mRNA is mediated through TNF-alpha. The FASEB Journal 463.11; 2006.
- 2.Anuradha Guggilam, Masudul Haque, Pamela Lucchesi and Joseph Francis. Cytokines modulate oxidative stress in ischemia reperfusion-induced heart injury in rats: Role of gp91phox and its homologues, Nox1 and Nox4.The FASEB Journal 735.12; 2006.
- 3. Eleonora Tobaldini, Alberto Porta, Nicola Montano, Joseph Francis, Shun-Guang Wei, Robert Weiss, Zhi-Hua Zhang, Robert Felder. Assessment of blood pressure variability by means of spectral and symbolic analysis in normal and congestive heart failure rats. The FASEB Journal 748.10; 2006. S.
- Julie Hartfield, Anuradha Guggilam, Masudul Haque, Inder Seghal and Joseph Francis. Angiotensin II Induced Hypertensive Response Is Modulated Through Tumor Necrosis Factor-alpha: Role Of Nox1, Nox4 And Gp91phox. High Blood Pressure Council Meeting, Abstract; 2005.
|
|