Are We βARKing Up the Right Tree?
Hypertension is a common disorder with complex etiology and particularly high prevalence among black Americans. Although the pathophysiologic mechanisms of essential hypertension are poorly understood, the disease is often associated with increased sympathetic nervous activity and elevated plasma norepinephrine levels. Such elevated plasma norepinephrine levels may, in turn, lead to increased adrenergic receptor activities in the cardiovascular system. The significance of the elevated plasma norepinephrine levels in the pathophysiologic mechanisms leading to increased blood pressure is uncertain.
In the present issue of Hypertension, Cohn et al1 report the novel findings that G protein-coupled receptor kinase 2 (βARK1/GRK2) levels and activities correlate with both blood pressure and plasma norepinephrine levels in a cohort of black Americans with normal blood pressure or with essential hypertension and metabolic syndrome but without other known chronic disease. Although a minority of the patients in the cohort actually had hypertension according to the current clinical definition, the study convincingly demonstrates that GRK2 expression correlates with systolic blood pressure. No correlation with blood pressure was found for any of the other common members of the GRK family. It will be interesting to see in the future to what extent increased GRK2 activities pertain only to black Americans with essential hypertension or to what extent the reported findings are pathophysiological responses common to hypertension among all races.
GRKs are enzymes that catalyze phosphorylation and desensitization of agonist-activated G protein-coupled receptors, now preferably denoted as 7 transmembrane segment receptors. Thus, the authors contend that increased GRK2 levels cause desensitization of β-adrenergic receptors (βAR) in vascular smooth muscle cells of resistance arteries and thereby decreased vasodilation in response to activation of βAR (Figure). This is an intriguing hypothesis, although the study does not resolve to what extent increased GRK2 levels actually contribute to increased peripheral resistance or merely mirror increased plasma norepinephrine activities. The observation that GRK2 levels correlate with systolic blood pressure may just reflect alterations in sympathetic nervous activity. In other words, the primary determinant of variations of blood pressure in the study cohort might be varying sympathetic nervous system outflow. Indeed, studies of the promoter of GRK2 have disclosed that activation of Gq-coupled 7 transmembrane segment receptors elicits signaling leading to activation of the GRK2 promoter and increased transcription of GRK2, eg, through postsynaptic α1-adrenergic receptors of the sympathetic nervous system.2 In this setting, increased GRK2 activities could serve as feedback inhibition.
However, depending on the substrate specificities of GRK2, it may also modify receptor activities in the vascular bed that might affect, eg, peripheral vascular resistance. Along this line of reasoning, increased GRK2 activities may indeed be a player in the pathophysiologic mechanisms of increased blood pressure or hypertension. A major limitation in our understanding of GRKs in physiological processes is that knowledge on the substrate specificities of the various GRK isoforms is lacking. GRK function has been studied mainly in immortalized, dedifferentiated cell lines, where GRK expression has been overexpressed. In such settings, the various GRK isoforms have revealed little evidence of distinct substrate specificities. On the contrary, eg, in differentiated cardiac myocytes, it was reported recently that GRK3 was highly selective for α1-ARs and endothelin receptors, whereas GRK2 displayed selectivity for the βAR.3 However, knowledge on the substrate specificities of the GRK isoforms in the vascular smooth muscle cells of resistance arteries is lacking. Yet, it should be possible to test to what extent alterations of GRK2 activities in vascular smooth muscle cells may play role in the pathophysiologic mechanisms of hypertension using conditional knockout or knock in of GRK2 in vascular smooth muscle cells. Such model systems are available and should be used to test the involvement of GRK2 in the control of blood pressure. Interestingly, single nucleotide polymorphisms of GRK3 and GRK5 have been reported to affect either expression levels or kinase activities of these isoforms and conceivably could affect blood pressure.4,5 However, knowledge on genetic polymorphisms leading to altered GRK2 activities is lacking.
Thus, the pathophysiologic involvement of GRK isoforms in cardiovascular disease is just beginning to be uncovered. Also, small molecule inhibitors of any of the GRKs are not yet available, but, if successful, could provide an important tool to decipher the functions of the various GRK isoforms in the cardiovascular system.
Sources of Funding
Supported by grants from The Research Council of Norway, The Norwegian Council on Cardiovascular Disease, and The South-Eastern Norway Regional Health Authority.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Cohn HI, Xi Y, Pesant S, Harris DM, Hyslop T, Falkner B, Eckhart AD. G protein-coupled receptor kinase 2 expression and activity are associated with blood pressure in black Americans. Hypertension. 2009; 54: 71–76.
Ramos-Ruiz R, Penela P, Penn RB, Mayor F Jr. Analysis of the human G protein-coupled receptor kinase 2 (GRK2) gene promoter: regulation by signal transduction systems in aortic smooth muscle cells. Circulation. 2000; 101: 2083–2089.
Vinge LE, Andressen KW, Attramadal T, Andersen GØ, Ahmed MS, Peppel K, Koch WJ, Freedman NJ, Levy FO, Skomedal T, Osnes JB, Attramadal H. Substrate specificities of G protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Mol Pharmacol. 2007; 72: 582–591.