Fig. 4. Cross-talk between ADT (GnRH agonists) and cGMP-mediated signaling: potential adverse events and possible preventive mechanisms.

GnRH agonists can regulate PKA signaling in cardiac cells via GnRHRs thereby altering the intracellular calcium. The altered calcium can lead to mitochondrial influx and induce cardiomyocyte apoptosis, eventually impairing cardiac contractility or causing heart failure. PDE5 inhibitors can upregulate NO in cardiac cells through constitutively active eNOS. The increased NO can upregulate cGMP which may protect cardiomyocytes through cGMP/PKG signaling and inhibition of mitochondrial calcium uptake. The GnRH agonists mediated potential CV events are given in the left box and the our perspective are given in the right box along with posssible mechanistic relation. The mitochondrion icon is from Servier Medical Art (http://smart.servier.com), licensed under Creative Common Attribution 3.0. (https://creativecommons.org/licenses/by/3.0/). Abbreviations : cGMP – cyclic guanosine monophosphate, eNOS – endothelial nitric oxide synthase, GC – guanylate cyclase, GTP – guanosine-5′-triphosphate, H₂S - hydrogen sulfide, iNOS – inducible NOS, mitoKATP - ATP-sensitive mitochondrial potassium channel, MPTP - membrane permeability transition pore, PDE5 – phosphodiesterase type 5, PKA – protein kinase A, PKG – protein kinase G, MPTP – mitochondrial permeability transition pore, NO – nitric oxide.