Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure

Abstract

Background: Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca -calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been 2q implicated as transducers of the hypertrophic response. Methods and results: To study whether the calcineurin pathway is activated in human heart failure, we investigated samples of human left ventricular myocardium from patients with dilated (idiopathic) cardiomyopathy (DCM, NYHA IV, ns8) in comparison with non-failing controls (NF, ns8). We not only analyzed the pathway by measuring the calcineurin activity, but also by determination of the protein expression of the calcineurin B subunit and additional key markers of the calcineurin signaling cascade (NFAT-3, GATA-4). Calcineurin enzymatic activity was increased by 80% in human dilated cardiomyopathy compared with non-failing human hearts (135.424"11.69 and 83.484"1.81 nmol Piymin per ml). This was in line with increased protein expression of calcineurin B in DCM (71.18q9.11 vs. 46.41"11.23 densitometric units (DU)ymg protein). In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT-3 in homogenates within nuclear extracts. In nuclear extracts the protein level of NFAT-3 was increased in dilated cardiomyopathy compared with non-failing myocardium (104.01"8.85 vs. 71.47"8.79 DUymg protein). In contrast, in homogenates the expression of NFAT-3 was higher in the non-failing tissue indicating subcellular redistribution (19.56"3.36 vs. 25.84"3.16 DUymg protein). The protein expression of GATA-4 was increased in DCM (43.14"2.89 vs. 29.87"2.17 DUymg protein). Conclusions: In human heart failure (DCM) the calcineurin signaling pathway is activated not only by an increased activity of calcineurin and expression of GATA-4, but also by the shift from dephosphorylated NFAT-3 to the nucleus indicating subcellular redistribution and regulatory activation.

Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy

“…9,10 Increases in CAN activity and/or expression also are reported in other animal models 11 and in patients 12 with structural heart disease. Pharmacological CAN inhibition reduces cardiac hypertrophy in CAN-overexpressing mice 9 but surprisingly does not reduce mortality or improve left ventricular (LV) function, 13 which suggests that other signals may persist even after CAN inhibition that are critical for increased mortality in CAN cardiomyopathy.…”

Activation of the Calcineurin/NFAT Signalling Cascade Starts Early in Human Hypertrophic Myocardium

“…4). In a meta-regression analysis that included our data from endstage human heart failure, 12 this linear correlation was also present (data not shown).…”

“…10,11 Furthermore, we recently showed an increased calcineurin activity, an increased expression of calcineurin B, GATA-4 and a nuclear translocation of NFAT-3 in the failing human heart with dilated cardiomyopathy. 12 Aside from these data on the calcineurin pathway in the terminally failing human heart there are a lack of data regarding its involvement in the earlier stages of the disease process, i.e. myocardial hypertrophy.…”

Efeito do treinamento físico nas adaptações estruturais cardíacas em um modelo genético de cardiomiopatia induzida por hiperatividade simpática

“…Além do envolvimento da via da calcineurina na hipertrofia cardíaca em modelos experimentais de doenças cardiovasculares, essa via está ativada em pacientes com insuficiência cardíaca, tanto em estágios iniciais (Diedrichs et al, 2007) como avançados da doença (Lim & Molkentin, 1999;Diedrichs et al, 2004;Diedrichs et al, 2007) o que demonstra a relevância clínica do estudo desta via no remodelamento cardíaco na síndrome da insuficiência cardíaca antes e após o uso de estratégias terapêuticas com o intuito de promover remodelamento cardíaco reverso e melhora na função contrátil.…”

“…Além dos dados morfológicos e morfométricos cardíacos, também avaliamos a expressão de genes envolvidos na reprogramação fetal (genes somente expressos em fases de desenvolvimento embrionário do tecido cardíaco e reprimidos no período pós-natal) que têm sido utilizados como marcadores moleculares da transição de hipertrofia compensada para insuficiência cardíaca (Hasegawa et al, 1997;Herzig et al, 1997;Sadoshima & Izumo, 1997;Thum et al, 2007 (Diedrichs et al, 2007), ou avançados da síndrome (Lim & Molkentin, 1999;Diedrichs et al, 2004;Diedrichs et al, 2007 (Sussman et al, 1998;Meguro et al, 1999;Lim et al, 2000). No entanto, seu uso clínico é restrito pelos efeitos colaterais da ciclosporina (Crespo-Leiro, 2005).…”