Targeting multidrug resistance proteins to promote cytoprotective cyclic GMP signalling in heart failure

Cyclic-3’,5’-guanosine monophosphate (cGMP) is a fundamental intracellular signalling molecule underpinning the biological actions of nitric oxide (NO) and natriuretic peptides, and key to cardiovascular homeostasis.

Termination of the functional signal conveyed by cGMP is primarily dependent on hydrolysis by phosphodiesterase isozymes, but cellular efflux has been postulated to play a role; cell-based studies imply this latter phenomenon can be fulfilled by multidrug resistance proteins (MRPs).

Herein, the effect of selective pharmacological targeting or genetic deletion of MRPs in vascular smooth muscle cells in vitro, isolated vessels and hearts ex vivo, in vivo and in an experimental models of heart failure (HF) will be investigated with respect to cGMP-driven responses (e.g. cell proliferation, vasodilatation, cardiac function) triggered by both NO and natriuretic peptides.

Biochemical assessment of intra:extra –cellular cGMP ratios will be assessed to provide mechanistic insight.

Findings from the work should establish the potential for MRP inhibition to promote the cardio- and vaso- protective actions of NO and/or natriuretic peptides.

Consequently, repurposing of MRP inhibitors (e.g. probenecid) may have therapeutic utility in cardiovascular diseases associated with dysfunctional cGMP signalling, by promoting the beneficial actions of this cyclic nucleotide which are established in left ventricular (LV) and right ventricular (RV) failure.