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Sickle cell anemia (SCA) can lead to a host of complications, including hemolysis, vaso-occlusive episodes (painful crises), pulmonary hypertension, acute chest syndrome, and multiorgan damage. SCA has no widely available cure. Furthermore, the available treatments have unfavorable side effects, such as myelosuppression of blood cells from continuous use of hydroxyurea, iron overload from repeated blood transfusions, or immunosuppressive treatments required to sustain a bone marrow transplant. In patients with SCA, hemoglobin-induced damage of endothelial cells can lead to endothelial dysfunction due to the deficiency of nitric oxide (NO) [1]. NO is continuously synthesized by the endothelium to maintain vascular tone. The NO-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMaP) pathway is one of the three important signaling pathways that are regulated by NO in maintaining the vascular tone. NO stimulates sGC in the vascular smooth muscle cells to induce formation of cGMP. This produced cGMP causes stimulation of cGMP-dependent protein kinases (cGKs), which in turn stimulate voltagedependent ion channels. The cGKs are serene and threonine kinases, substrates for cGMP to elicit physiological functions. cGKs inhibit calcium release from the endoplasmic reticulum through the inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) and alternatively activate myosinlight-chain phosphatase by inhibiting the MLC kinases, with both mechanisms resulting in smooth muscle relaxation [2]. Two types of cGKs have been revealed to date. Mammalian cGKs exist as two isoforms, cGKI and cGKII, which are coded by the prkg1 and prkg2 genes, respectively. In humans two isoforms of cGKI have been described, cGKI-α and cGKI-β, differing only in their N-terminal parts and generated by alternative splicing of a single gene. Northern blot analysis revealed that human cGKI-α mRNA was present in the aorta, heart, kidneys, and adrenal glands. In contrast, human cGKI-β mRNA was present only in the uterus. In SCA, vascular tone control is compromised due to vasculopathy associated with hemolysis. As NO is considered beneficial, hydroxyurea and inhalational NO were administered to increase the bioavailability of NO, which raises cGMP levels [3]. Phosphodiesterases (PDEs) are enzymes that catalyze cGMP to GMP. Inhibitors of PDEs also increase cGMP levels by decreasing the degradation of cGMP. Inhibition of PDE9A enzyme with the specific inhibitor BAY73-6691 reversed the increased adhesive properties of neutrophils in sickle cell disease and increased production of the γ-globin gene (HBG) in K562 cells. Furthermore, sGC activators were suggested for treatment of sickle cell disease (Figure 1) [4]. 1Sri Ramachandra Medical College and Research Institute-DU, Faculty of Medicine, Department of Pharmacology, Chennai, Tamil Nadu, India 2Sickle Cell Institute Chhattisgarh, Department of Molecular Genetics, Division of Research, Raipur, Chhattisgarh, India Mohankrishna Ghanta1, Elango Panchanathan1, Bhaskar VKS Lakkakula2 Siklik Guanozin Monofosfat Bağımlı Protein Kinaz I Uyarıcıları ve Aktivatörleri Orak Hücreli Anemide Tedavi Alternatifleridir Cyclic Guanosine Monophosphate-Dependent Protein Kinase I Stimulators and Activators Are Therapeutic Alternatives for Sickle Cell Disease