Rapid Aldosterone Signaling in Vascular Smooth-Muscle Cells - Involvement of Phospholipase-C, Diacylglycerol and Protein-Kinase-C-α

Christ, Michael; Meyer, Christiane; Sippel, Katrin; Wehling, Martin

doi:10.1006/bbrc.1995.2106

Cited by 108 publications

(58 citation statements)

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“…Our data add to the growing literature describing rapid, nongenomic effects of aldosterone (2,5,(32)(33)(34)(35). For example, aldosterone activates signaling pathways such as PKA, PKC, PKD, MAPK, and the NADPH oxidase in vascular smooth muscle; and aldosterone activates phosphatidylinositol 3-kinase in endothelial cells (32,34,(36)(37)(38)(39)(40)(45)(46)(47). However, nongenomic effects of aldosterone can be mediated through either the MR or other unidentified proteins.…”

Section: Aldosterone Activates Endothelial Exocytosis Through a Nongementioning

confidence: 58%

Aldosterone activates endothelial exocytosis

Jeong¹,

Chaupin²,

Matsushita³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although elevated levels of aldosterone are associated with vascular inflammation, the proinflammatory pathways of aldosterone are not completely defined. We now show that aldosterone triggers endothelial cell exocytosis, the first step in leukocyte trafficking. Exogenous aldosterone stimulates endothelial exocytosis of Weibel-Palade bodies, externalizing P-selectin and releasing von Willebrand factor. Spironolactone, a nonselective mineralocorticoid receptor (MR) blocker, antagonizes aldosterone-induced endothelial exocytosis. Knockdown of the MR also decreases exocytosis, suggesting that the MR mediates exocytosis. Aldosterone triggers exocytosis within minutes, and this effect is not inhibited by actinomycin D, suggesting a nongenomic effect of aldosterone. Aldosterone treatment of endothelial cells increases leukocyte adherence to endothelial cells in culture. Taken together, our data suggest that aldosterone activates vascular inflammation in part through nongenomic, MR-mediated pathways. Aldosterone antagonism may decrease vascular inflammation and cardiac fibrosis in part by blocking endothelial exocytosis.inflammation ͉ mineralocorticoid ͉ P-selectin ͉ vascular ͉ nitric oxide

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Section: Aldosterone Activates Endothelial Exocytosis Through a Nongementioning

confidence: 58%

Aldosterone activates endothelial exocytosis

Jeong¹,

Chaupin²,

Matsushita³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Because classic PKCs are implicated in the mediation of aldosterone signaling, 23 we investigated activation of PKC isoforms in NRCMs and CFs after treatment with aldosterone. The most notable effect was phosphorylation of PKD, which was serine residue specific and cyclic ( Figure 5A).…”

Section: Signal Transducers Of Hypertrophic and Fibrotic Effects Of Amentioning

confidence: 99%

Aldosterone, Through Novel Signaling Proteins, Is a Fundamental Molecular Bridge Between the Genetic Defect and the Cardiac Phenotype of Hypertrophic Cardiomyopathy

et al. 2004

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Background-Human hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. The genetic basis of HCM is largely known; however, the molecular mediators of cardiac phenotypes are unknown. Methods and Results-We show myocardial aldosterone and aldosterone synthase mRNA levels were elevated by 4-to 6-fold in humans with HCM, whereas cAMP levels were normal. Aldosterone provoked expression of hypertrophic markers (NPPA, NPPB, and ACTA1) in rat cardiac myocytes by phosphorylation of protein kinase D (PKD) and expression of collagens (COL1A1, COL1A2, and COL3A1) and transforming growth factor-␤1 in rat cardiac fibroblasts by upregulation of phosphoinositide 3-kinase (PI3K)-p100␦. Inhibition of PKD and PI3K-p110␦ abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor (MR) antagonist spironolactone. Spironolactone reversed interstitial fibrosis, attenuated myocyte disarray by 50%, and improved diastolic function in the cardiac troponin T (cTnT)-Q92 transgenic mouse model of human HCM. Myocyte disarray was associated with increased levels of phosphorylated ␤-catenin (serine 38) and reduced ␤-catenin-N-cadherin complexing in the heart of cTnT-Q92 mice. Concordantly, distribution of N-cadherin, predominantly localized to cell membrane in normal myocardium, was diffuse in disarrayed myocardium. Spironolactone restored ␤-catenin-N-cadherin complexing and cellular distribution of N-cadherin and reduced myocyte disarray in 2 independent randomized studies. Conclusions-The results implicate aldosterone as a major link between sarcomeric mutations and cardiac phenotype in HCM and, if confirmed in additional models, signal the need for clinical studies to determine the potential beneficial effects of MR blockade in human HCM.

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“…Moreover, several rapid aldosterone-induced changes of the concentration of intracellular second messengers have been described. 6,10,11 Aldosterone is reported to activate protein kinase C (PKC) in distal colon cells and cultured kidney cells and to decrease its activity stimulated by phorbol-12-myristate-13-acetate in rat neonatal cardiomyocytes. [12][13][14] However, there is no clear consensus whether PKC is involved in the nongenomic effects of aldosterone on the vascular tone of coronary arteries in the ischemic hearts.…”

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confidence: 99%

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

et al. 2005

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Abstract-Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4Ϯ3.8 to 19.3Ϯ5.2 mL/100 g/min; PϽ0.05), along with decreases in fractional shortening (FS) (8.4Ϯ0.7 to 5.4Ϯ0.4%; PϽ0.05) and lactate extraction rate (LER) (Ϫ31.7Ϯ2.9 to Ϫ41.4Ϯ3.7%; PϽ0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKCdependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects. Key Words: aldosterone Ⅲ ischemia Ⅲ protein kinases A ldosterone modulates cardiovascular function in addition to the crucial role in sodium and potassium homeostasis through binding to the intracellular mineralocorticoid receptors (MRs). 1 These receptor-mediated effects with transcriptional modulation of target genes are termed genomic effects. 2 Recently, another pathway possibly mediated by the specific membrane receptors through which aldosterone acts, ie, nongenomic effects of aldosterone, has been investigated. [2][3][4] Although this nongenomic action of aldosterone was shown in a variety of tissues such as vascular smooth muscle cells or cardiomyocytes, the effects of aldosterone on vascular tone are divergent. 4 -9 Aldosterone increased systemic vascular resistance in humans, as shown in the first report on the nongenomic effects of aldosterone, whereas aldosterone inhibits vasoconstriction in renal afferent arterioles. 7-9 Until now, the rapid nongenomic effects of aldosterone on vascular tone of coronary artery and cardiac functions in vivo under ischemia are not still fully estimated. Moreover, several rapid aldosterone-induced changes of the concentration of intracellular second messengers have been described. 6,10,11 Aldosterone is reported to activate pro...

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Rapid Aldosterone Signaling in Vascular Smooth-Muscle Cells - Involvement of Phospholipase-C, Diacylglycerol and Protein-Kinase-C-α

Cited by 108 publications

References 0 publications

Aldosterone activates endothelial exocytosis

Aldosterone activates endothelial exocytosis

Aldosterone, Through Novel Signaling Proteins, Is a Fundamental Molecular Bridge Between the Genetic Defect and the Cardiac Phenotype of Hypertrophic Cardiomyopathy

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

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