Therapeutic Modulation of Nitric Oxide Pathways to Address Insulin Resistance in Cardiovascular–Kidney–Metabolic Syndrome

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  Figure 1. Complementary vascular and cellular mechanisms linking nitric oxide signaling to insulin action. (A) Vascular cGMP-dependent mechanism. Activation of endothelial insulin receptors stimulates the PI3K/Akt/eNOS pathway and NO production. NO diffuses into vascular smooth muscle cells, activates sGC, promotes the conversion of GTP to cGMP, and activates PKG, thereby increasing vasodilation and skeletal muscle perfusion. (B) Cellular cGMP-independent mechanism. NO-mediated S-nitrosylation of PTP1B, SHP-1, and SHP-2 inhibits protein tyrosine phosphatase activity, limits IRS dephosphorylation, and supports IRS/PI3K/Akt signaling. This promotes GLUT4 translocation, glucose uptake, and cellular insulin sensitivity. Abbreviations: Akt, protein kinase B; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; GLUT4, glucose transporter type 4; GTP, guanosine triphosphate; IRS, insulin receptor substrate; NO, nitric oxide; PI3K, phosphoinositide 3-kinase; PKG, protein kinase G; PTP, protein tyrosine phosphatase; PTP1B, protein tyrosine phosphatase 1B; sGC, soluble guanylate cyclase; SHP-1 and SHP-2, Src homology 2 domain-containing protein tyrosine phosphatases 1 and…

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  Figure 2. Selective endothelial insulin resistance and imbalance between PI3K/Akt/eNOS and MAPK signaling. Under physiological conditions, insulin activates the endothelial PI3K/Akt/eNOS pathway, promoting eNOS phosphorylation at Ser1177, NO production, cGMP generation in vascular smooth muscle cells, and vascular relaxation. In insulin-resistant states, this pathway is selectively impaired, whereas MAPK signaling remains preserved or becomes enhanced during compensatory hyperinsulinemia. The resulting increases in ET-1 production, VCAM-1 and E-selectin expression, and vascular smooth muscle cell proliferation shift the endothelium toward a vasoconstrictive and pro-inflammatory phenotype. Reduced NO availability combined with increased ET-1 signaling impairs vasodilation and microvascular recruitment while increasing vascular tone, permeability, inflammation, and remodeling. Abbreviations: Akt, protein kinase B; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PI3K, phosphoinositide 3-kinase; Ser1177, serine 1177; VCAM-1, vascular cell adhesion molecule 1; VSMC, vascular smooth…

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  Figure 3. Emerging therapeutic strategies targeting nitric oxide bioavailability and signaling in insulin resistance and cardiovascular–kidney–metabolic syndrome. The proposed approaches include: (1) arginase inhibition to preserve L-arginine availability for eNOS-dependent NO production; (2) enhancement of DDAH-mediated ADMA degradation to relieve endogenous NOS inhibition; (3) microbiome-dependent bioactivation of dietary nitrate through the nitrate–nitrite–NO pathway; (4) pharmacological modulation of sGC–cGMP–PKG signaling to promote vasodilation; (5) enhancement of eNOS expression or activity through transcriptional enhancers, modulation of the hemoglobin-α/eNOS interaction, and Cavnoxin-like peptides; and (6) modulation of erythrocyte-mediated NO homeostasis, including the proposed contribution of S-nitrosohemoglobin to NO bioactivity at the endothelium. These strategies remain predominantly preclinical or at an early translational stage. Abbreviations: ADMA, asymmetric dimethylarginine; cGMP, cyclic guanosine monophosphate; CKM, cardiovascular–kidney–metabolic; DDAH, dimethylarginine dimethylaminohydrolase; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; Hbα,…