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REVIEW

Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska

Submitted January 22, 2009 ; accepted in final form August 24, 2009

ABSTRACT

Angiotensin type 1 receptors (AT₁Rs) 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 AT₁Rs 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 AT₁R regulation in the setting of chronic heart failure (CHF). There is now good evidence that AT₁R 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 AT₁R expression and transcription factor activation can be blocked by the AT₁R antagonist losartan, a positive feedback mechanism of AT₁R 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 AT₁R expression by altering the balance between the octapeptide ANG II and ANG- (1–7). Finally, exercise training reduces both central oxidative stress and AT₁R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter AT₁R expression in CHF.

sympathetic nerve activity; neuronal signaling; oxidative stress