An "I" on cardiac hypertrophic remodelling: imidazoline receptors and heart disease.

The centrally-acting sympatholytic imidazoline compound, moxonidine, prevents the development of left ventricular hypertrophy and attenuates maladaptive proliferative signalling as well as downstream apoptotic pathways in spontaneously hypertensive rat and cardiomyopathic hamster hearts. The actions are selectively mediated by imidazoline type-1 receptor (I(1)-receptor, also named nischarin), nonadrenergic neurotransmitter receptors mainly found in the brainstem medulla. We identified cardiac I(1)-receptors/nischarin and showed that they are upregulated in cardiovascular disorders, and are functional without the central nervous system's contribution. Molecular characterization revealed that I(1)-receptor/nischarin has a unique structure with multifunctional domains allowing it to perform a number of cell signalling roles as a scaffolding protein. Nischarin has been associated with integrin α5 and inhibition of Rac1 and was shown to interact with insulin receptor substrates. However, very little is known about cardiac I(1)-receptor/nischarin and its role(s) in normal physiology and pathophysiology, specifically in cardiac remodelling. Our studies have shown that I(1)-receptor is expressed in cardiac fibroblasts and myocytes and that in vitro I(1)-receptor activation inhibits norepinephrine-induced cardiomyocyte apoptosis and fibroblast proliferation, through differential effects on mitogen-activated protein kinases and Akt. Accordingly, apart from centrally-mediated sympatholytic function, I(1)-receptor in the heart may control cell growth and death. I(1)-receptor may be implicated in cardiac remodelling and dysfunction, through the inhibition of apoptotic pathways and/or activation of survival pathways, in a cell-specific manner. Identification of the cardioprotective mechanisms of cardiac I(1)-receptor could result in specifically-tailored cell/gene-driven I(1)-receptor treatments, and/or treatments that target cardiac I(1)-receptor, which could eventually be important for patients with hypertrophic heart disease.