Cardiac and Vascular α1-Adrenoceptors in Congestive Heart Failure: A Systematic Review

Abstract

As heart failure (HF) is a devastating health problem worldwide, a better understanding and the development of more effective therapeutic approaches are required. HF is characterized by sympathetic system activation which stimulates α- and β-adrenoceptors (ARs). The exposure of the cardiovascular system to the increased locally released and circulating levels of catecholamines leads to a well-described downregulation and desensitization of β-ARs. However, information on the role of α-AR is limited. We have performed a systematic literature review examining the role of both cardiac and vascular α1-ARs in HF using 5 databases for our search. All three α1-AR subtypes (α1A, α1B and α1D) are expressed in human and animal hearts and blood vessels in a tissue-dependent manner. We summarize the changes observed in HF regarding the density, signaling and responses of α1-ARs. Conflicting findings arise from different studies concerning the influence that HF has on α1-AR expression and function; in contrast to β-ARs there is no consistent evidence for down-regulation or desensitization of cardiac or vascular α1-ARs. Whether α1-ARs are a therapeutic target in HF remains a matter of debate.

Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha1-adrenoceptors to early cardiac stress responses

“…Pro-inotropic effects occurred despite the downregulation of α 1A/B -AR mRNA levels, indicating a sufficient α 1A/B -AR receptor reserve in mice. Interestingly, reduction in α 1 -AR mRNA expression was either similarly (α 1A/B -AR) or exclusively (α 1D -AR) affected by ISO alone, substantiating the concept that unlike β 1/3 -ARs, α 1 -AR expression levels might be independent of chronic agonist exposure [35]. Of note, while meanBP was similar in both models, lower expression of cardiac α 1D -AR mRNA under ISO conditions may suggest that coronary blood flow could be differently affected [68], although the functional consequences of this reduction are yet to be further investigated.…”

“…While α 1 -AR-dependent activation of adaptational responses such as the re-expression of fetal genes e.g., involved in sarcomere structure and function ( Acta1 , Myh7 , Xirp2 , Pdlim5 ) is a long-standing concept, α 1 -ARs have been reported to mediate a much more global impact on cardiac stress responses including non-cardiomyocytes. This is especially interesting because apart from smooth muscle cells, α 1 -ARs were mostly reported absent in other non-cardiomyocyte cell populations [ 35 ]. However, cardiomyocyte-specific α 1A -AR overexpression was shown to drive progressive fibrosis and reactivation of genes encoding matricellular proteins in the absence of pharmacological or surgical interventions [ 6 ], and angiogenesis after myocardial infarction [ 80 ], indicating a potential role for α 1 -AR signaling in cell–cell communication and organ homeostasis.…”

“…They lack the effects of released co-transmitters such as neuropeptide Y [ 64 ] and in case of ISO/PE, the impact on the coronary microvasculature where α 2 -ARs predominate [ 25 , 26 ]. In addition, differences between species regarding the distribution, densitiy and function of adrenergic receptors may have to be considered [ 4 , 35 ]. Lastly, the α 1 -AR agonist PE also shows affinity to β 2 -AR, but with fourtyfold higher EC 50 values than ISO [ 52 ].…”

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe

“…Given that catecholamine levels are elevated and b 1 ARs are selectively downregulated, while b 2 ARs are also dysfunctional, that is, incapable of coupling to G proteins (see above), cardiac a 1 AR effects may become extremely important in the failing heart. Indeed, a 1 ARs stimulate 'adaptive' or 'physiological' cardiac hypertrophy without fibrosis or other manifestations of adverse remodeling, while preserving cardiac function and even inducing myocyte proliferation with ventricular muscle wall thickening [78][79][80][81]. Nevertheless, there are also several studies arguing for the opposite; that is, that cardiac a 1 ARs mediate maladaptive cardiac hypertrophy by inducing b-myosin heavy chain and other maladaptive gene expression (activation of the 'fetal gene program' of cardiac adverse remodeling) [80].…”

Cardiac cAMP-PKA Signaling Compartmentalization in Myocardial Infarction

“…Among α-ARs, α1-AR and α2-AR are involved in the regulation of cardiac function. The α1-AR signals through Gα q stimulation and phospholipase C activation [ 53 ]. In presynaptic nerves, α2-AR coupled to Gα i/o inhibits AC activity and reduces catecholamine release ( Table 1 ) [ 54 ].…”