Science

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Under normal physiological conditions native nitric oxide (NO) stimulates soluble Guanyl Cyclase (sGC) to produce cGMP which, acting as a modulator of various protein kinases, controls the distribution of intracellular Ca++ and attenuates downstream both pro-osteogenic and pro-fibrotic signaling. 

 However, in diseased human aortic valves oxidative stress is elevated (Miller et al, 2008).: 

• Reactive oxygen species (ROS) such as superoxide (O3) and hydrogen peroxide (H2O2­) are markedly elevated in calcified regions of human stenotic vales. 
•  Antioxidant enzymes responsible for ROS metabolisms, such as superoxidase dismutase (SOD) (all three isoforms) and catalase, are reduced in peri-calcific regions compared to adjacent normal tissue.

Due to this oxidative stress, sGC is converted from its native form to the oxidized form which is insensitive to NO resulting in decreased levels of cGMP. This leads to an accumulation of intracellular calcium and valve calcification (Zhou et al, 2008) which underlies the progression of valve stenosis. Ataciguat, being a highly potent and specific activator of the oxidized form of sGC, reactivates downstream NO targets (Figure below). This is reflected by an ataciguated-mediated attenuation of osteogenic signaling and restoration of the role of protective pathways that are disrupted in valvular cells subjected to oxidative stress. In a preclinical animal model of CAVS, ataciguat via activation of oxidized soluble, NO-insensitive Guanylate Cyclase, led to the attenuation of BMP2-induced transcriptional responses resulting in a slowing of the accumulation of valvular calcium.  

Because ataciguat is able to specifically activate the oxidized form of sGC and because the oxidized form of sGC is specifically elevated in diseased aortic valves, we posit that this drug is endowed with a site- and event-specific advantage in its ability to restore NO signaling, attenuate osteogenic signaling and attenuate the progression of calcium accumulation responsible for valvular stenosis. In summary, fundamental biology underlying the pathogenesis of aortic valve calcification and stenosis provides the basis for the potential clinical application of ataciguat in CAVS.