Calcineurin in Human Heart Hypertrophy

Abstract

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 reversetranscription 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.

Molecular Diagnostics of Calcineurin-Related Pathologies

“…Assessment by Ritter et al of Cn activity and the NFAT phosphorylation state in tissue acquired from patients with hypertrophic cardiomyopathy revealed an increase in Cn capacity, as well as an increased electrophoretic mobility of NFATc1. Their results also suggest that Cn may undergo calpain-mediated truncation of its autoinhibiting carboxyl end after persistent activation, as is the case in the etiology of cardiac hypertrophy (71,72 ).…”

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

“…CaN, a calcium-regulated phosphatase, is activated in heart failure (22)(23)(24). Moreover, cain/cabin1 may bind to CaN and inhibit its activity (11)(12)(13).…”

Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

“…PP2B activity appears to be important for proliferation and hyperthrophic growth because: (1) inhibition of PP2B by VIVIT or CsA arrested the proliferation of VSMC (present study and Yellaturu et al 15 ); (2) PP2B can activate hypertrophic signals both in vitro in neonatal myocytes and in vivo in transgenic mice 32 as well as in the myocardium of patients with pressure overload. 33 Inactivation of PP2B by SERCA2a expression has at least 1 major consequence that is inhibition of NFAT transcriptional activity. SERCA2a does not affect the CaMKII in agreement with the notion that this pathway is more dependent on Ca 2ϩ influx.…”