Melusin Promotes a Protective Signal Transduction Cascade in Stressed Hearts

Abstract

Melusin is a chaperone protein selectively expressed in heart and skeletal muscles. Melusin expression levels correlate with cardiac function in pre-clinical models and in human patients with aortic stenosis. Indeed, previous studies in several animal models indicated that Melusin plays a broad cardioprotective role in different pathological conditions. Chaperone proteins, besides playing a role in protein folding, are also able to facilitate supramolecular complex formation and conformational changes due to activation/deactivation of signaling molecules. This role sets chaperone proteins as crucial regulators of intracellular signal transduction pathways. In particular Melusin activates AKT and ERK1/2 signaling, protects cardiomyocytes from apoptosis and induces a compensatory hypertrophic response in several pathological conditions. Therefore, selective delivery of the Melusin gene in heart via cardiotropic adenoviral associated virus serotype 9 (AAV9), may represent a new promising gene-therapy approach for different cardiac pathologies.

Keywords: AKT; ERK 1/2; HSP90; Melusin; apoptosis; chaperone; heart failure; intracellular signaling.

Figure 1

Melusin cardioprotective role in the heart. Melusin protects the heart from “maladaptive remodeling” during mechanical stress. Melusin potentiates the compensatory hypertrophic response of the heart preserving its contractile function. Melusin also prevents cardiac dilation and fibrosis deposition and protects cardiomyocytes from apoptotic death.

Figure 2

Melusin-dependent activation of ERK1/2 and AKT under mechanical stress. Under mechanical stretch condition, Melusin binds to the cytoplasmic domain of β1-integrin and interacts with IQGAP1, leading to the activation of ERK1/2 and AKT cardioprotective pathways.