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

Abstract

The angiotensin (Ang) II/Ang II receptor (ATR)-associated calcium signaling pathway is the major cause of ventricular remodelling in patients with congestive heart failure (CHF). However, the calcium-regulated proteinases responsible for Ang II-induced remodelling are not well understood. We investigated the profiles of the Ang II/ATR/calpain/calcineurin (CaN) pathway in human failing heart. We measured both the plasma and cardiac levels of Ang II and cardiac mRNA expression of ATR in 39 patients with CHF and 38 healthy controls. Importantly, protein expression of calpains, cleavage of cain/cabin1 and activity of CaN were tested. Both plasma and cardiac levels of Ang II were significantly increased in patients with CHF (both p<0.01), and the plasma Ang II concentration was closely correlated with the parameters of ventricular remodelling (r=±0.29-0.65, p<0.05 or <0.01). In addition, the cardiac level of AT1R but not AT2R was significantly upregulated in mild failing hearts (p<0.05) but dramatically downregulated in severe failing ones (p<0.01). CHF was associated with a marked upregulation of calpains, an increased cleavage of cain/cabin1, and the activation of CaN in the failing ventricular tissue. In patients with CHF, calpain upregulation was associated with an increase in cleavage of cain/cabin1 and the activation of CaN, indicating that these changes in calciumregulated proteinases contribute to Ang II-induced cardiac remodelling.