Protein Kinase C as a Modulator of Response Amplification in Vascular Smooth Muscle

Laher, Ismail; Thompson, Loren P.; Gagne, Lisa

doi:10.1159/000158827

Cited by 7 publications

(7 citation statements)

References 20 publications

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“…We found that a subcontractile concentration of endothelin-1 or angiotensin II potentiated the contractile response to phenylephrine in vitro. This is in agreement with previous studies that have demonstrated the occurrence of the phenomenon in vitro [15][16][17][18]22,23 or in vivo, 14,19 -21 as well as in humans. 14,20 -23 We have previously shown that this potentiation involves a sensitization of the contractile apparatus to calcium through the activation of protein kinase C. 15,17 Furthermore, we and others have also previously reported that endogenous endothelin-1 25 and angiotensin II 19 -21 take part in the control of vascular tone in resistance arteries and that the concentrations of hormones used in the present study are compatible with endogenous concentrations.…”

Section: Iglarz Et Al Preproendothelin-1 Gene and Vascular Tonediscussupporting

confidence: 93%

Preproendothelin-1 Gene Polymorphism Is Related to a Change in Vascular Reactivity in the Human Mammary Artery In Vitro

et al. 2002

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Abstract-A gene polymorphism of preproendothelin-1 (a G-to-T transversion that predicts a Lys/Asn change at codon 198) associated with an increased risk of hypertension has been recently described in patients carrying the T allele. No study has yet determined the impact of this polymorphism on vascular reactivity, although a functional role for endothelin-1 in the pathophysiology of hypertension has been clarified. At subthreshold concentrations, endothelin-1 and angiotensin II induce a potentiation of ␣-adrenergic-dependent vascular tone caused by an increased sensitivity of the contractile apparatus to calcium. We investigated phenylephrine-induced tone and its amplification by endothelin-1 and angiotensin II in human mammary artery rings in vitro. Contractions to phenylephrine (0.1 to 100 mol) and endothelin-1 (0.1 to 300 nmol) were not significantly different in rings from GT/TT (nϭ27) and GG (nϭ21) patients. A subthreshold concentration of endothelin-1 (10 pmol) potentiated a phenylephrine-induced contraction (eg, 44Ϯ12% increase in tone with phenylephrine 1 mol/L, PϽ0.001) that was significantly higher in the GT/TT group than in the GG group (eg, 44Ϯ12% versus 82Ϯ11%, PϽ0.01). A similar effect on response to phenylephrine was observed with a subthreshold concentration of angiotensin II. We also found a higher response to calcium in arteries from GT/TT patients. Endothelium-dependent or -independent relaxations were unaffected by the genotype. These data suggest that the preproendothelin-1 gene polymorphism is associated with a higher potentiating effect of endothelin-1 and angiotensin II, probably in relation with higher calcium sensitivity. These changes in vascular reactivity might help to understand the relations between this polymorphism and cardiovascular disorders. Key Words: blood vessels Ⅲ polymorphism Ⅲ endothelin Ⅲ phenylephrine Ⅲ angiotensin II A gene polymorphism of preproendothelin-1 has been described as a G-to-T transversion at position 5665 affecting the 61st nucleotide of exon 5, which predicts a Lys/Asn change at codon 198. Among the several epidemiological studies performed, one has shown that this polymorphism was associated with a higher blood pressure in overweight patients with the T allele. 1 If gene polymorphisms have to be considered in the physiopathology of cardiovascular diseases, the knowledge of their vascular effects remains a key issue. Indeed, no study has yet been conducted to determine the functional impact of this polymorphism on vascular function.A key role for endothelin-1 in the control of vascular tone has been described in different types of blood vessels, and its role in several pathological situations has been clarified. [2][3][4][5][6][7][8][9][10][11][12][13] At subthreshold concentrations, within the physiological (picomolar) range, endothelin-1 has no direct contractile effect but induces a potent amplification of ␣-adrenergicdependent vascular tone. 14,15 This amplification by endothelin-1 involves a sensitization of the contractile apparatus to calcium 15 a...

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Section: Iglarz Et Al Preproendothelin-1 Gene and Vascular Tonediscussupporting

confidence: 93%

Preproendothelin-1 Gene Polymorphism Is Related to a Change in Vascular Reactivity in the Human Mammary Artery In Vitro

et al. 2002

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“…Indeed, in support of a postsynaptic effect of ET-1, Tabushi et al 6 have shown that ET-1 potentiated norepinephrine-induced contractions together with a decrease in the release of norepinephrine from the rat mesenteric artery. Laher et al 21 have suggested that tonic modulation of PKC activity increases the sensitivity of intracellular contractile mechanisms associated with Ca ^-dependent vasoconstriction, providing a nonspecific mechanism for agonist amplification. The present study showed that staurosporine and calphostin C, two mechanistically distinct inhibitors of PKC, suppress the amplifying effect of ET-1.…”

Section: Discussionmentioning

confidence: 99%

“…In all cases, they did not affect the norepinephrine-induced contraction. Moreover, in such conditions, they presumably do not inhibit myosin light chain kinase activity since they do not influence the response to readmission of Ca 2+ in the depolarized rabbit femoral artery, 21 basilar artery, 22 and aorta, 15 as well as in rat midcerebral artery and mesenteric arterioles. 23 Biochemical 24 and functional studies 14 - 15 have shown that calphostin C is more specific for PKC than staurosporine.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of norepinephrine-induced contractions by endothelin-1 in the rabbit aorta.

Henrion

Laher

1993

Hypertension

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Subthreshold concentrations of endothelin-1 potentiated the norepinephrine-induced contraction in isometrically mounted rings of the rabbit aorta. Pretreatment with endothelin-1 (0.1 nM) for 10 minutes increased the sensitivity of the aortic rings to norepinephrine without affecting the maximal contraction. This amplification was unaffected by removal of the endothelium but was prevented by the protein kinase C inhibitors staurosporine (0.01 (iM) and calphostin C (0.1 fiM). Pretreatment of the aortic rings for 24 hours with phorbol 12-myristate 13-acetate (0.1 fiM) also abolished the potentiation. Norepinephrineinduced contraction was potentiated by pretreating with phorbol 12-myristate 13-acetate (10 nM) and by increasing the concentration of K + in the bath solution from 4.6 to 8.6 mM. The potentiation of the norepinephrine-induced contraction by endothelin-1 (0.1 nM) or by phorbol 12-myristate 13-acetate (10 nM) was not associated with an increase in norepinephrine-induced 45 Ca 2+ uptake or influx, whereas the potentiation due to an increase in the concentration of K + in the bath solution from 4.6 to 8.6 mM was associated with an increase in norepinephrine-induced 45 Ca 2+ uptake. We conclude that endothelin-1 potentiation of the norepinephrine-induced contraction occurs in the absence of changes in stimulated Ca 2+ entry and is endothelium independent. It is probable that endothelin-1 increases the sensitivity of the contractile apparatus to Ca 2+ by activating protein kinase C-dependent mechanisms. produced by endothelial cells. 1 Its direct contractile effect has been widely studied, although it is not yet completely understood.2 On the other hand, subthreshold concentrations of ET-1, compatible with the plasma level, 3 potentiate the contractile effect of different agonists such as norepinephrine in human arteries 4 and rat mesenteric beds 5 -6 and serotonin in rat aortic rings 7 and pulmonary arteries. 8 Such a phenomenon might have a pathological importance since it could be involved in hypertension and vasospastic syndrome.4 Indeed, the potentiation of serotonininduced contractions by ET-1 might increase the vasospasms induced by aggregating platelets. Moreover, there is a positive correlation between ET-1 plasma level and systolic blood pressure in humans, 9 and the vascular production of ET-1 under angiotensin II (Ang II) stimulation is higher in hypertensive than in normotensive rats. 10 The amplification is nevertheless blocked by Ca 2+ entry blocker in human arteries 4 and in the rat mesenteric bed. 6 In contrast, the direct effect of ET-1 is relatively insensitive to Ca 2+ entry blockers.

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“…The two steps in the catalytic cycle of the "reciprocating" enzyme, sACE. stimulates expression of, or sensitivity to, potent pressors such as endothelin [86], thrombin [87][88][89], thromboxane [90], epinephrine [91], and EPO [92]. Angiotensin II stimulates thrombosis in a number of ways: by inducing expression of the thrombin receptor and potentiating the action of thrombin [87][88][89], by stimulating the release of platelet activating factor (PAF) [93], and by stimulating platelet aggregation and adhesion directly [94][95][96][97].…”

Section: Angiotensin II Vs Nomentioning

confidence: 99%

The Central Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology

Moskowitz¹,

Johnson²

2004

CTMC

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Genomic epidemiologic data, increasingly supported by clinical outcomes results, strongly suggest that overactivity of angiotensin I-converting enzyme (ACE) may underlie most age-related diseases. Angiotensin II, the main product of ACE, is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. So it is perhaps not surprising that the ACE D/D genotype is associated with several major psychiatric diseases, most cancers except prostate cancer (where the D/D genotype is actually protective), most cardiovascular diseases, most autoimmune diseases, and even infectious diseases like tuberculosis and HIV. In a preliminary study, angiotensin II blockade appeared to hasten recovery from West Nile virus encephalitis; it may be equally useful in SARS. The ACE gene underwent duplication at the origin of Chordata, just before the "Cambrian Explosion" in the number of species. The ancestral, unduplicated form of ACE is still expressed during the terminal differentiation of human spermatocytes, suggesting a critical role in reproduction. The crystal structure of testicular ACE (tACE) was recently published. Computer modeling suggests that tACE may be activated by both mechanical forces and reducing agents. The duplicated form of ACE (somatic ACE, sACE) is expressed in areas of high fluid flow. sACE may auto-dimerize via a novel protein motif, the "disulfide zipper." The sACE dimer is predicted to have higher catalytic efficiency and redox resistance than tACE.

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Protein Kinase C as a Modulator of Response Amplification in Vascular Smooth Muscle

Cited by 7 publications

References 20 publications

Preproendothelin-1 Gene Polymorphism Is Related to a Change in Vascular Reactivity in the Human Mammary Artery In Vitro

Preproendothelin-1 Gene Polymorphism Is Related to a Change in Vascular Reactivity in the Human Mammary Artery In Vitro

Potentiation of norepinephrine-induced contractions by endothelin-1 in the rabbit aorta.

The Central Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology

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