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

Abstract

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...

Effect of Endothelin 1 Genotype on Blood Pressure Is Dependent on Physical Activity or Fitness Levels

“…The same allele has been reported previously to be associated with elevated resting DBP in obese Japanese subjects, 9 elevated resting and exercise SBP in overweight whites, 10 increased BP reactivity to a video game challenge, 12 and with increased in vitro vascular reactivity. 28 Therefore, our novel discovery of a significant relationship between rs5370 and SBP responsiveness to endurance training is concordant with existing data on other hemodynamic phenotypes, ie, the T allele is associated with a less favorable hemodynamic profile. The functional significance of rs5370 is not clear at this time.…”

Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants

“…Its widespread potential effects include modification of risk for HTN in the overweight/obese population (41-43), BP reactivity to stressors (44)(45)(46), idiopathic pulmonary arterial Figure 4. Comparison in European descent subjects and African descent subjects of aldosterone/renin ratio was obtained on a restricted salt diet.…”

Endothelin-1 Gene Polymorphisms rs5370, rs1476046, and rs3087459 are not Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus

“…Of the studied polymorphisms, the rs5730 polymorphic variant was associated with blood pressure in overweight people of European 22 and Japanese descent 23 . Iglarz et al confi rmed the impact of rs5370 polymorphism on vascular reactivity 28 , while Treiber et al demonstrated that the rs5370 polymorphism infl uences blood pressure response to behavioral stress in obese subjects from lower socio-economic status 51 . Li et al identifi ed the Asn/Asn genotype of EDN1 rs5370 polymorphism as a genetic factor for delayed onset of T2DM and reduced risk of diabetic retinopathy in T2DM patients of Chinese descent.…”

“…EDN1 has been identifi ed as a strong candidate gene for cardiovascular and renal disease. Various single nucleotide polymorphisms (SNPs) in the EDN1 gene were linked to arterial hypertension 22,23 , heart failure 24 , coronary artery disease 25,26 , left ventricular hypertrophy 27 , modifi cation of vascular reactivity 28 , endothelial dysfunction 29 , progression of atherosclerosis 30 , as well as with accelerated decline in kidney function in the chronic glomerulonephritis patients 31 , and with end stage renal disease attributed to hypertension 32 . In addition, EDN1 genetic variability was related to microvascular complications of T2DM such as diabetic retinopathy 33 , and DN 34 .…”