3. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells

Hatakeyama, Hyōe; Miyamori, Isamu; Fujita, Tomoyuki; Takeda, Yoshiyu; Takeda, Ryuji; Yamamoto, Hiroshi; Gómez-Sánchez, Elise P.

doi:10.1007/bf03349773

Cited by 120 publications

(156 citation statements)

References 18 publications

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“…Poly(A) + RNAs were isolated [21] from cells treated for various time periods with or without AGE-BSA, and analyzed by RT-PCR as described previously [25]. After the RT-PCR, 6-ml aliquots of each reaction mixture were electrophoresed on 2 % agarose gels, and transferred to Hybond-N + nylon membranes, which were then hybridized with the respective 32 P-end labelled probes [19].…”

Section: Methodsmentioning

confidence: 99%

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

et al. 1998

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Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure which are common complications in patients with prolonged diabetes [1±3]. Plasminogen activator inhibitor-1 (PAI-1) is an important fast-acting serine protease inhibitor that attenuates fibrinolysis [4]. Epidemiological studies have demonstrated that reduced fibrinolytic activity because of elevated plasma PAI-1 is an important factor in various thrombotic diseases such as deep vein thrombosis, ischaemic heart disease [5±8] and diabetic vascular complications [9±10]. In addition to the attenuated fibrinolytic activity, hypercoagulability and platelet hyperaggregation are also prevalent in diabetic patients, contributing to microthrombus formation in diabetic micro-and macroangiopathies [11]. The molecular mechanisms underlying these thrombogenic abnormalities, however, are not fully understood. Diabetologia (1998) Summary Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI 2 ), an anti-thrombogenic prostanoid, and of plasminogen activator inhibitor-1 (PAI-1), a fast-acting serine protease inhibitor of fibrinolysis, in human microvascular endothelial cells (EC). Firstly, AGE-bovine serum albumin (BSA) but not non-glycated BSA, was found to considerably decrease the production of PGI 2 to about two-thirds of the control value. Secondly, quantitative reverse transcription-polymerase chain reaction showed that AGE-BSA increased the EC levels of mRNA coding for PAI-1, this being associated with a concomitant increase in the immunoreactive PAI-1 contents and the anti-fibrinolytic activity. Thirdly, the effects of AGE on PGI 2 and PAI-1 syntheses in EC were found to be mediated by a receptor for AGE (RAGE) because antisense DNA against RAGE mRNA could reverse the AGE effects. Further, it was found that AGE decreased the intracellular cyclic AMP concentrations in EC and that cyclic AMP agonists such as dibutyryl cyclic AMP, forskolin and PGI 2 analogue reduced the AGE-stimulated PAI-1 production, suggesting the involvement of cyclic AMP in the AGE-signalling pathway. The results thus suggest that AGE have the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis and thereby contributing to the development and progression of diabetic vascular complications.[ Diabetologia (1998

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Section: Methodsmentioning

confidence: 99%

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

et al. 1998

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“…Aldosterone may also be generated in the heart and blood vessels, although there is controversy on whether the amounts produced are physiologically relevant. The classical target of aldosterone is the distal convoluted tubule of the kidney, where it acts on cytosolic mineralocorticoid receptors (MRs) that translocate to the nucleus and via different mechanisms (serum and glucocorticoid-induced kinase-1 [SGK-1], neural precursor cell expressed developmentally downregulated 4 [nedd4], nedd4 isoform 2 [nedd4-2], K-Ras2A, and capsaicin) 1 modulating the epithelial sodium channel and renal outer medullary potassium channels to induce increased reabsorption of sodium and excretion of potassium, thus regulating sodium, potassium, and body fluid balance.…”

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“…Aldosterone has been reported to be synthesized, 4 MRs demonstrated, 5 and the presence of the cortisol-inactivating enzyme 11-␤-hydroxysteroid-dehydrogenase-2 identified in blood vessels. 6 However, the production of aldosterone by blood vessels and the heart remains controversial (see below).…”

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Effects of Aldosterone on the Vasculature

2006

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“…6 We reported that aldosterone, synthesized in the vasculature, is in part controlled by angiotensin (Ang) II and participates in the development of vascular hypertrophy that correlates with Ang II concentration. 7,8 We performed the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibitor, and Ang II on aldosterone synthesis, aldosterone synthase activity, and the expression of aldosterone synthase gene (CYP11B2) in the heart. Next, to clarify the pathophysiological roles of cardiac aldosterone in the hypertensive heart, we compared both aldosterone synthesis and the expression of CYP11B2 mRNA in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats.…”

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Cardiac Aldosterone Production in Genetically Hypertensive Rats

et al. 2000

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Abstract-Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [ 14 C]deoxycorticosterone to [ 14 C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2-and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats. (Hypertension. 2000;36:495-500.)Key Words: heart Ⅲ rats, inbred strains Ⅲ aldosterone Ⅲ hypertrophy Ⅲ cytochrome p450 Ⅲ mRNA A ldosterone receptors are present in cardiac myocytes, endocardial endothelial cells, and cardiac fibroblasts. 1 The peripheral infusion of aldosterone in rats causes cardiac hypertrophy and cardiac fibrosis without increasing the blood pressure. 2 In cultured neonatal rat fibroblasts or cardiomyocytes, aldosterone increases collagen synthesis and protein synthesis. 3,4 Physiologically significant amounts of mineralocorticoids are believed to be synthesized only in the adrenal cortex. However, extra-adrenal steroid 21-hydroxylation and 11␤-hydroxylation occur in a variety of human tissues. Circulating progesterone is converted to deoxycorticosterone (DOC) and DOC sulfate in adult and fetal human extra-adrenal tissues. 5 The extra-adrenal expression of steroid 21-hydroxylase and 11␤-hydroxylase by a benign testicular Leydig cell tumor has also been reported. 6 We reported that aldosterone, synthesized in the vasculature, is in part controlled by angiotensin (Ang) II and participates in the development of vascular hypertrophy that correlates with Ang II concentration. 7,8 We performed the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibitor, and Ang ...

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3. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells

Cited by 120 publications

References 18 publications

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

Effects of Aldosterone on the Vasculature

Cardiac Aldosterone Production in Genetically Hypertensive Rats

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