The impact of blunted beta-adrenergic responsiveness on growth regulatory pathways in hypertension.
The effects of vasodilator hormones acting through receptors linked to adenylyl cyclase are impaired in the hypertensive state. This has been ascribed to impaired receptor-G protein coupling. However, these receptors also act via effectors not linked to adenylyl cyclase activation. These "alternate" mechanisms may be especially important in growth regulation and might be unaffected (or enhanced) with G protein-coupled receptor-G protein uncoupling. Therefore, we assessed the effects of beta-adrenergic activation on 1) regulation of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated kinase (ERK) activation-two tyrosine kinase-dependent enzymes linked to cell growth-and 2) microarray analysis in vascular smooth muscle cells from spontaneously hypertensive rats (SHR). Isoproterenol-stimulated phosphorylation of ERK1/2 was impaired in SHR. The effect of forskolin was unaltered. In contrast, both vasopressin and angiotensin 2-mediated stimulation of ERK activation was enhanced in SHR. In addition, beta-adrenergic-mediated inhibition of PI3 kinase activity was attenuated in SHR (whereas the effect of forskolin remained intact). In microarray studies, the effect of isoproterenol to regulate transcription was significantly impaired in SHR (as was the effect of forskolin). Together, these data support the hypothesis that the blunted vasodilator effects of hormones linked to adenylyl cyclase activation are an index of a more generalized impairment in modulating growth regulatory pathways. Furthermore, this study supports the hypothesis that the blunting of beta-adrenergic responses relating to increased G protein-coupled receptor kinase 2 expression reflects a "generalized uncoupling" of beta-adrenergic-mediated responses and do not support the concept of "enhanced coupling" of "alternate" pathways of beta-adrenergic growth regulatory pathways in the hypertensive state.
Gros
Robert
R
Cell Signaling Research Group, Robarts Research Institute, 100 Perth Dr., London, ON, Canada N6A 5K8.
Ding
Qingming
Q
Chorazyczewski
Jozef
J
Andrews
Joseph
J
Pickering
J Geoffrey
JG
Hegele
Robert A
RA
Feldman
Ross D
RD
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D017931:DNA Primers; D010982:Platelet-Derived Growth Factor; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol