The carotid body (CB) chemoreflex is enhanced in chronic heart failure (CHF) and contributes to the chronic elevation in sympathetic nerve activity (SNA). This enhanced functionality is driven by an increased activity from CB chemoafferents, resulting from alterations in redox signaling within the CB from enhanced angiotensin II (Ang II) -NADPH oxidase - super oxide anion (O2*""""""""), and attenuated neural and endothelial nitric oxide synthase (nNOSI/eNOS) - nitric oxide (NO) that synergistically inhibit Kv* channel currents in CB glomus cells and increase excitability. Recent evidence suggests Ang 1-7 derived from ACE2, inhibits CB chemoafferent activity and is down regulated by CHF. Exercise training (ExT) reverses these alterations in CB function in CHF. The stimuli for these altered signaling pathways in the CB in CHF and their reversal with ExT is unknown. We propose in Aim 1 that Ang 1-7 produced in the CB normally acts via the Mas receptor to activate nNOS - NO production in glomus cells to restrain excitability, via activation of Kv* currents and inhibition of high voltage activated Ca** currents. We propose that CHF downregulates ACE2 while up regulating ACE to shift Ang metabolism away from Ang 1-7/NO toward Ang 11/ O2"""""""" signaling at glomus cells to promote enhanced afferent function. The relative contributions of ACE and ACE2 to CB function in CHF will be tested.
In Aim 2. we propose the fundamental hypothesis that a chronic decrease in CB blood flow (CBF) due to cardiac failure and CB vasoconstriction alters endothelial ACE, ACE2 and NOS function in the CB to effect the altered Ang/NO signaling at glomus cells discussed above. We propose that upregulation of ACE, and downregulation of ACE2 / eNOS expression in the CB in CHF is caused by a decreased transcriptional activity of the kruppel like factor 2 (KLF2) triggered by a reduction in shear stress on CB endothelial cells. Lastly, we hypothesize in Aim 3 that the normalizing effect of ExT on CB function in CHF is brought about by regular periodic increases in CBF during exercise to improve endothelial KLF2, ACE, ACE2 and eNOS, expression, and thus, restore normal Ang/NO balance and control of K*/Ca** channels in glomus cells, effecting CB function. These hypotheses will be tested at four levels: integrative (CB chemoreflex changes in SNA and ventilation);tissue (CB chemoafferent discharge);cellular (ion channel currents in CB glomus cells);and molecular (mRNA/protein expression in the CB, immunohistochemistry for localization), using genomic (overexpression of mediators via viral vectors localized to the CB) and pharmacological approaches in models of pacing-induced CHF and of chronic reduced CBF in rabbits.
This proposal addresses the molecular pathway for altered CB function in CHF via the angiotensin and nitric oxide systems. We propose these changes result from reduced blood flow to the CB in CHF to alter endothelial expression of ACE, ACE2 and NOS via the KLF2 transcription factor. Furthermore, the beneficial effect of ExT on CB function in CHF may result from improved blood flow to the CB. Outcomes may impact clinical management of CHF through more targeted pharmacological/genomic approaches and a better understanding of the actions of exercise as a therapeutic modality. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Performance
|Tian, Changhai; Gao, Lie; Zimmerman, Matthew C et al. (2018) Myocardial infarction-induced microRNA-enriched exosomes contribute to cardiac Nrf2 dysregulation in chronic heart failure. Am J Physiol Heart Circ Physiol 314:H928-H939|
|Marcus, Noah J; Del Rio, Rodrigo; Ding, Yanfeng et al. (2018) KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure. J Physiol 596:3171-3185|
|Fontes, Marco Antônio Peliky; Vaz, Gisele Cristiane; Cardoso, Thais Zielke Dias et al. (2018) GABA-containing liposomes: neuroscience applications and translational perspectives for targeting neurological diseases. Nanomedicine 14:781-788|
|de Morais, Sharon D B; Shanks, Julia; Zucker, Irving H (2018) Integrative Physiological Aspects of Brain RAS in Hypertension. Curr Hypertens Rep 20:10|
|Zheng, Hong; Katsurada, Kenichi; Liu, Xuefei et al. (2018) Specific Afferent Renal Denervation Prevents Reduction in Neuronal Nitric Oxide Synthase Within the Paraventricular Nucleus in Rats With Chronic Heart Failure. Hypertension 72:667-675|
|Lewis, Robert; Hackfort, Bryan T; Schultz, Harold D (2018) Chronic Heart Failure Abolishes Circadian Rhythms in Resting and Chemoreflex Breathing. Adv Exp Med Biol 1071:129-136|
|Becker, Bryan K; Wang, Hanjun; Zucker, Irving H (2017) Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats. Auton Neurosci 205:77-86|
|Zheng, Hong; Liu, Xuefei; Li, Yulong et al. (2017) A Hypothalamic Leptin-Glutamate Interaction in the Regulation of Sympathetic Nerve Activity. Neural Plast 2017:2361675|
|Sharma, Neeru M; Nandi, Shyam S; Zheng, Hong et al. (2017) A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure. Am J Physiol Heart Circ Physiol 312:H968-H979|
|Mishra, Paras K; Ying, Wei; Nandi, Shyam Sundar et al. (2017) Diabetic Cardiomyopathy: An Immunometabolic Perspective. Front Endocrinol (Lausanne) 8:72|
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