Abstract
cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced heart failure was also explored. MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP per se but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio in vitro and in vivo. MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity. This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
Highlights
CGMP is a common intracellular second messenger responsible for conveying many of the cardiovascular actions of NO and natriuretic peptides (Kuhn, 2016; Papapetropoulos et al, 2015)
These findings suggest that efflux of cGMP through MRP4/MRP5 (i.e. MK571-inhibitable multidrug resistance protein (MRP)) regulates the cellular response of human coronary artery smooth muscle cell (hCASMC) to NO donors and atrial natriuretic peptide (ANP), but that activation of the membrane-spanning GC-A by ANP is subject to significant cGMP efflux that is sensitive to MRP blockade
This has been postulated based on cell- and tissue-based systems and understood to involve, at least in part, MRP4 and/or MRP5, gap junctions may fulfil this remit, Bevans et al, 1998
Summary
CGMP is a common intracellular second messenger responsible for conveying many of the cardiovascular actions of NO and natriuretic peptides (Kuhn, 2016; Papapetropoulos et al, 2015). The discrete localisation of these synthetic and degradatory enzymes enables compartmentalisation of cGMP-regulated processes to distinct cellular localities This phenomenon has been established largely in cardiomyocytes and vascular smooth muscle cells (VSMCs) through the utilisation of cGMP-specific FRET sensors (Calamera et al, 2019; Russwurm & Koesling, 2018; Sinha et al, 2013; Subramanian et al, 2018; Thunemann et al, 2013) and by functional pharmacological assessment of selelective GC ligands (i.e. NO vs natriuretic peptides) and PDE inhibitors (Baliga et al, 2018; Bubb et al, 2014; Kokkonen & Kass, 2017; Moltzau et al, 2014; Zhao et al, 1999). This proliferative profile was explored in the absence and presence of MK571 (30 nM to 30 μM), ANP (100 nM), the NO donor diethylenetriamine-NONOate (Deta-NO; 10 μM) or combinations thereof
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