Angiotensin Receptors in Cardiovascular Diseases

Brown, Lindsay; Sernia, Conrad

doi:10.1111/j.1440-1681.1994.tb02450.x

Cited by 27 publications

(8 citation statements)

References 62 publications

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“…Thus, the number of AT1 receptors defines the biological efficacy of angiotensin II. The RAS has also been implicated in cardiovascular pathology, and the upregulation of AT1 receptors in the cardiovascular system has been reported in diseases like thyroid dysfunction, hypertension and myocardial infarction [22][23][24]. Our present findings demonstrate increased densities of the AT1 receptor mRNA and protein in human atrial myocardium of patients suffering from type 2 diabetes.…”

Section: Discussionsupporting

confidence: 71%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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Aims/hypothesis The angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin-angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients. Methods Gene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II. Results Diabetic myocardium showed a significant increase in protein expression (170±16% of control) and median mRNA expression (186% of control) of the AT1 receptor.The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89±5.5% vs 29±1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression. Conclusions/interpretation AT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients.

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Section: Discussionsupporting

confidence: 71%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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“…Both local production of ANG II and AT 1 receptor expression are increased in cardiac myocytes and preglomerular vessels in streptozotocin-induced diabetic rats (3,42). Also, AT 1 receptor expression has been shown to be increased in the kidney and/or VSM cells in experimental models of hypertension, cyclosporin nephrotoxicity, and myocardial infarction (5,6,9,15,18,26,27). Of interest, both diabetes and hypertension, including cyclosporin administration, have been shown to produce tissue hypoxia (40,50,52).…”

mentioning

confidence: 99%

Hypoxia and high glucose upregulate AT₁receptor expression and potentiate ANG II-induced proliferation in VSM cells

Sodhi¹,

Kanwar

Sahai³

2003

American Journal of Physiology-Heart and Circulatory Physiology

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We examined the effect of hypoxia and high glucose (HG) on ANG II type 1 (AT 1) receptor expression and proliferation in cultured vascular smooth muscle (VSM) cells. Exposure of quiescent cells to hypoxia in a serum-free DME-Ham's F-12 medium for 6-24 h induced a progressive increase in AT 1 mRNA expression. Exposure of cells to 24 h of hypoxia also resulted in a significant increase in ANG II receptor binding as assessed with 125 I-labeled ANG II. Treatment with ANG II (1 M) for 24 h under normoxic conditions caused an ϳ1.5-fold increase in both DNA synthesis and cell number, which was enhanced to ϳ3.0-fold under hypoxic conditions. An AT 1 receptor antagonist (losartan, 10 M) blocked the ANG II-induced increase in DNA synthesis under both normoxic and hypoxic conditions. Incubations in HG medium (25 mM) for 12-24 h under normoxic conditions induced an ϳ2.5-fold increase in AT 1 mRNA levels, which was markedly enhanced by hypoxia to ϳ5.5-fold at 12 h and ϳ8.5-fold at 24 h. ANG II under HG-normoxic conditions caused a complete downregulation of AT 1 expression, which was prevented by hypoxia. These results demonstrate an upregulation of AT 1 receptor expression by hypoxia and HG in cultured VSM cells and suggest a mechanism for enhanced ANG II-induced VSM cell proliferation and the development of atherosclerosis in diabetes. vascular smooth muscle cells; diabetes; chronic hypoxia; cell growth; angiotensin II receptor ARTERIAL WALL HYPOXIA and the associated vascular smooth muscle (VSM) cell proliferation have been implicated in the development of atherosclerosis (7, 23). Moreover, we recently reported (43) that hypoxia directly induces the proliferation of cultured rat aortic VSM cells. Others have shown that hypoxia is also mitogenic to cultured pulmonary artery smooth muscle and endothelial cells (12,13,25). Prevalence of tissue hypoxia and increased VSM cell proliferation is also reported in experimental models of diabetes and hypertension (1,10,28,35,40,45). Elevated glucose concentrations in medium have been shown to produce both hypertrophic and hyperplastic effects in cultured porcine aortic smooth muscle cells (32). We found (43, 44) that high medium glucose also induces the proliferation of cultured VSM cells as well as renal glomerular mesangial cells. In addition, hypoxia potentiates the effect of high medium glucose on the proliferation of both VSM and mesangial cells (43,44). Together, these results strongly suggest an important role for local hypoxia in accelerated VSM cell proliferation in diabetes. The mechanisms responsible for the accelerated VSM cell growth and progression into cardiovascular disease in diabetes remain to be clearly defined.Activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of vascular complications of diabetes (16). The primary active component of the RAS, ANG II, causes hypertrophy, hyperplasia, and the deposition of extracellular matrix proteins in VSM cells (19,21,36,49). Interestingly, ANG II-induced proliferation of cultured rat ...

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“…4,6 However, in preliminary studies it produced only a weak, if any, constrictor response in human omental arteries. The possibility that the capacity of the AT 1 -receptor is underestimated under these assay conditions was therefore examined.…”

Section: Introductionmentioning

confidence: 99%

“…1,3 All the well-known vasomotor effects of Ang II are mediated by AT 1 -receptors. 4,5 Thus, blockade of AT 1 -receptors may leave the AT 2 -receptor untouched and able to mediate potentially beneficial effects on the vasculature.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries

Ytterberg¹,

Edvinsson

2001

J Renin Angiotensin Aldosterone Syst

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Enhanced responses to vasoconstriction induced by neuropeptide Y and α 2 -adrenoceptor agonists have been seen following pharmacological activation of the adenylyl cyclase (AC) system. Since preliminary studies revealed only minor responses to angiotensin II (Ang II) in human omental arteries, we have investigated whether enhanced activity of AC may unravel further functional Ang II receptors. Human omental arteries were obtained in conjunction with elective gut surgery. After dissection of the vessel, the endothelium was removed by 10 sec of Triton X-100 treatment. Ring segments (1-2 mm long) were mounted on a myograph and studied. Ang II produced small contractions, 27±5% relative to the response elicited by 60 mM K + . However, enhanced Ang II (105±10%, p<0.001) responses were seen during AC activation by forskolin (0.1-1 µM). This enhanced contractile response to Ang II was not inhibited by the angiotensin II type 2 (AT 2 -receptor antagonist PD 123319 (0.1 µM), but was blocked in an insurmountable way by the angiotensin II type 1 (AT 1 )-receptor antagonist candesartan (1 nM) and in a surmountable manner by losartan (0.1 µM) and irbesartan (0.1 µM). Pertussis toxin (a Gi-protein blocker) and the protein kinase C inhibitor, RO31-8220 (0.01, 0.1 and 1 µM), markedly reduced this response, while the protein kinase A inhibitor, H89 (1, 10 µM), had no effect. RT-PCR provided evidence for the presence of mRNA for both AT 1 -and AT 2 -receptors. The results suggest that both a cAMP-dependent and a cAMP-independent mechanism are involved in the contractile responses to Ang II in human omental arteries and that both responses are mediated via the AT 1 -receptor.

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Angiotensin Receptors in Cardiovascular Diseases

Cited by 27 publications

References 62 publications

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

Hypoxia and high glucose upregulate AT₁receptor expression and potentiate ANG II-induced proliferation in VSM cells

Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries

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Angiotensin Receptors in Cardiovascular Diseases

Cited by 27 publications

References 62 publications

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

Hypoxia and high glucose upregulate AT1receptor expression and potentiate ANG II-induced proliferation in VSM cells

Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries

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Hypoxia and high glucose upregulate AT₁receptor expression and potentiate ANG II-induced proliferation in VSM cells