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   AT2 receptor activation regulates myocardial eNOS expression via the calcineurin-NF-AT pathway.; ; et al in FASEB Journal (2003), 17(2), 283-5 The role of AT2-receptors has recently been subject of considerable debate. We investigated the influence of AT2-stimulation/inhibition on myocardial endothelial NO-synthase (eNOS, NOS-III) promoter ... [more ▼] The role of AT2-receptors has recently been subject of considerable debate. We investigated the influence of AT2-stimulation/inhibition on myocardial endothelial NO-synthase (eNOS, NOS-III) promoter activity and eNOS protein expression. Stimulation of rat cardiomyocytes with angiotensin II (AngII) increased eNOS protein expression 3.3-fold. This was blocked by Cyclosporin A (CsA). Inhibition of the AT1-receptor did not reduce AngII-mediated eNOS protein expression, whereas AT2 stimulation increased it 2.4-fold and AT2 inhibition suppressed it. The modulatory effects of the AT2-receptor on eNOS expression was confirmed in mice with a genetic deletion of the AT2-receptor (AT2-KO). In gel shift assays two putative NF-AT sites in a 1.6 kb eNOS promoter fragment showed NF-AT binding and a supershift by NF-AT2(-c1)-specific antibodies. Stimulation of transfected cells with AngII or specific AT2-receptor agonists resulted in a significant increase in eNOS promoter activity, which was blocked by CsA, MCIP1, and mutation of an upstream NF-AT site. CONCLUSION: 1) AngII-stimulation of the myocardium, both in vivo and in vitro, is accompanied by increased expression of eNOS. 2) This effect is mediated by the calcineurin pathway and is induced by the AT2-receptor. 3) These results define a calcineurin/NF-AT/eNOS pathway as downstream effector of AT2-receptor activation in the myocardium. [less ▲] Detailed reference viewed: 203 (1 UL)Calcineurin in human heart hypertrophy.; ; et al in Circulation (2002), 105(19), 2265-9 BACKGROUND: In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be ... [more ▼] BACKGROUND: In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. METHODS AND RESULTS: We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. CONCLUSIONS: Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy. [less ▲] Detailed reference viewed: 197 (0 UL) |
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