Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure.
Angiotensin type 1 receptors (AT(1)Rs) play a critical role in a variety of physiological functions and pathophysiological states. They have been strongly implicated in the modulation of sympathetic outflow in the brain. An understanding of the mechanisms by which AT(1)Rs are regulated in a variety of disease states that are characterized by sympathoexcitation is pivotal in development of new strategies for the treatment of these disorders. This review concentrates on several aspects of AT(1)R regulation in the setting of chronic heart failure (CHF). There is now good evidence that AT(1)R expression in neurons is mediated by activation of the transcription factor activator protein 1 (AP-1). This transcription factor and its component proteins are upregulated in the rostral ventrolateral medulla of animals with CHF. Because the increase in AT(1)R expression and transcription factor activation can be blocked by the AT(1)R antagonist losartan, a positive feedback mechanism of AT(1)R expression in CHF is suggested. Oxidative stress has also been implicated in the regulation of receptor expression. Recent data suggest that the newly discovered catabolic enzyme angiotensin-converting enzyme 2 (ACE2) may play a role in the modulation of AT(1)R expression by altering the balance between the octapeptide ANG II and ANG- (1-7). Finally, exercise training reduces both central oxidative stress and AT(1)R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter AT(1)R expression in CHF.
Zucker
Irving H
IH
Dept. of Cellular and Integrative Physiology, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA. izucker@unmc.edu
Schultz
Harold D
HD
Patel
Kaushik P
KP
Wang
Wei
W
Gao
Lie
L
D000803:Angiotensin I; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002908:Chronic Disease; D015444:Exercise; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)