Pulmonary arterial hypertension: Sex matters.

Pulmonary arterial hypertension (PAH) is a complex disease of multifactorial origin. While registries have demonstrated that women are more susceptible to the disease, females with PAH have superior right ventricle (RV) function and a better prognosis than their male counterparts, a phenomenon referred to as the 'estrogen paradox'. Numerous pre-clinical studies have investigated the involvement of sex hormones in PAH pathobiology, often with conflicting results. However, recent advances suggest that abnormal estrogen synthesis, metabolism and signalling underpin the sexual dimorphism of this disease. Other sex hormones, such as progesterone, testosterone and dehydroepiandrosterone may also play a role. Several non-hormonal factor including sex chromosomes and epigenetics have also been implicated. Though the underlying pathophysiological mechanisms are complex, several compounds that modulate sex hormones levels and signalling are under investigation in PAH patients. Further elucidation of the estrogen paradox will set the stage for the identification of additional therapeutic targets for this disease.

Animal models of pulmonary hypertension: Getting to the heart of the problem.

Despite recent therapeutic advances, pulmonary hypertension (PH) remains a fatal disease due to the development of right ventricular (RV) failure. At present, no treatments targeted at the right ventricle are available, and RV function is not widely considered in the preclinical assessment of new therapeutics. Several small animal models are used in the study of PH, including the classic models of exposure to either hypoxia or monocrotaline, newer combinational and genetic models, and pulmonary artery banding, a surgical model of pure RV pressure overload. These models reproduce selected features of the structural remodelling and functional decline seen in patients and have provided valuable insight into the pathophysiology of RV failure. However, significant reversal of remodelling and improvement in RV function remains a therapeutic obstacle. Emerging animal models will provide a deeper understanding of the mechanisms governing the transition from adaptive remodelling to a failing right ventricle, aiding the hunt for druggable molecular targets. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart and vasculature.

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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. LINKED ARTICLES: 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.