title: ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction.
abstract: Brain MAPK signaling pathways are activated in heart failure (HF) induced by myocardial infarction and contribute to augmented sympathetic nerve activity. We tested whether decreasing ERK1/2 (also known as p44/42 MAPK) signaling in the hypothalamic paraventricular nucleus (PVN), a forebrain source of presympathetic neurons, would reduce the upregulation of sympathoexcitatory mediators in the PVN and augmented sympathetic nerve activity in rats with HF. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce HF, with left ventricular dysfunction confirmed by echocardiography. One week after coronary artery ligation or sham operation, small interfering (si)RNAs targeting ERK1/2 or a nontargeting control siRNA was microinjected bilaterally into the PVN. Experiments were conducted 5-7 days later. Confocal images revealed reduced phosphorylated ERK1/2 immunofluorescence in the PVN of HF rats treated with ERK1/2 siRNAs compared with HF rats treated with control siRNA. Western blot analysis confirmed significant reductions in both total and phosphorylated ERK1/2 in the PVN of HF rats treated with ERK1/2 siRNAs along with reduced expression of renin-angiotensin system components and inflammatory mediators. HF rats treated with ERK1/2 siRNAs also had reduced PVN neuronal excitation (fewer Fos-related antigen-like-immunoreactive neurons), lower plasma norepinephrine levels, and improved peripheral manifestations of HF compared with HF rats treated with control siRNAs. These results demonstrate that ERK1/2 signaling in the PVN plays a pivotal role in mediating sympathetic drive in HF induced by myocardial infarction and may be a novel target for therapeutic intervention.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Shun-Guang
authors.initials: SG
authors.lastname: Wei
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa robert-felder@uiowa.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000378:metabolism; D004452:Echocardiography; D055785:Gene Knockdown Techniques; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000235:genetics*; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D009638:Norepinephrine / Q000097:blood; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D013564:Sympathetic Nervous System / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D034741:RNA, Small Interfering; D009638:Norepinephrine
keywords: autonomic regulation; brain; extracellular signal-regulated kinases 1 and 2; mitogen-activated protein kinase; proinflammatory cytokines; renin-angiotensin system