Phospholipase C epsilon 1 as a therapeutic target in cardiovascular diseases

Fig. 1. The catalyzed reaction and the domain structure of PLCε1. (A) PLCε1 promotes the hydrolysis of PIP2 on the plasma membrane to generate IP3 and DAG. IP3 induces Ca2+ release from intracellular stores, while DAG activates PKC. (B) PLCε1 consists of a PH domain, four tandem EF-hand domains, a catalytic TIM barrel domain (split by an autoregulatory “X-Y linker”), a C2 domain, two RA domains, and a CDC25 homology domain. (C) The structure of PLCε1 EF3-RA2 [32]. (D) Superimposing the RA1 domain in the EF3-RA1 structure with the RA2 domain in the H-Ras–RA2 structure indicated that the predicted GTPase binding surface on the RA1 domain is obstructed by the EF3/4 domains [32]. H-Ras is shown in dark grey, Mg2+ as a black sphere, and GTP in red sticks. PLCε1, phospholipase C epsilon 1; PIP2, phosphatidylinositol-4,5-bisphosphate; IP3, inositol-1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; PH, pleckstrin homology; TIM, triose-phosphate isomerase; RA, Ras-associating. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2. PLCε1-related signaling pathways in cardiac hypertrophy. Diagram showing proposed upstream regulators and downstream targets of PLCε1 in cardiac hypertrophy. PLCε1, phospholipase C epsilon 1; TAC, transverse aortic constriction; ET-1, endothelin-1; β-AR, β-adrenergic receptor; OCT3, organic cation transporter 3; cAMP, cyclic adenosine monophosphate; PDE, phosphodiesterase; PKA, protein kinase A; mAKAP, muscle-specific A-kinase anchoring protein; PI4P, phosphatidylinositol-4-phosphate; DAG, diacylglycerol; PKD, protein kinase D; CaMKII, calcium/calmodulin-dependent protein kinase II; HDAC, histone deacetylase.

Fig. 3. Potential PLCε1-related signaling pathways in hypertension. Diagram illustrating PLCε1 and its potentially related pathways implicated in hypertension. PLCε1, phospholipase C epsilon 1; Ang II, angiotensin II; ET-1, endothelin-1; VDC, voltage-dependent Ca2+ channels; ROC, receptor-operated Ca2+ channels; SOC, store-operated Ca2+ channels; TRP, transient receptor potential; IP3, inositol-1,4,5-trisphosphate; IP3R, IP3 receptor; RyR, ryanodine receptor; DAG, diacylglycerol; PKC, protein kinase C; CaM, calmodulin; MLC, myosin light-chain; MLCK, MLC kinase; CPI-17, C-kinase potentiated protein phosphatase 1 inhibitor, molecular mass 17 kDa; MLCP, MLC phosphatase.

Fig. 4. The correlative roles and mechanisms of PLCε1 across various cardiovascular diseases. PLCε1, phospholipase C epsilon 1; ET-1, endothelin-1; Ang II, angiotensin II; β-AR, β-adrenergic receptor; VDC, voltage-dependent Ca2+ channels; ROC, receptor-operated Ca2+ channels; SOC, store-operated Ca2+ channels; TRP, transient receptor potential; IP3, inositol-1,4,5-trisphosphate; IP3R, IP3 receptor; RyR, ryanodine receptor; CaMKII, calcium/calmodulin-dependent protein kinase II; DAG, diacylglycerol; PKD, protein kinase D; mAKAP, muscle-specific A-kinase anchoring protein; HDAC, histone deacetylase; PKC, protein kinase C; CaM, calmodulin; MLC, myosin light-chain; MLCK, MLC kinase; CPI-17, C-kinase potentiated protein phosphatase 1 inhibitor, molecular mass 17 kDa; MLCP, MLC phosphatase; SSH1L, slingshot protein phosphatase 1-like; Bax, Bcl-2 associated X protein; I/R, ischemia/reperfusion; ERK1/2, extracellular signal-regulated kinase 1/2; NF-κB, nuclear factor kappa B; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; ROS, reactive oxygen species; GSDME, Gasdermin E; DOX, doxorubicin.

Fig. 5. The roles and mechanisms of PLCε1 in cardiovascular diseases. PLCε1, phospholipase C epsilon 1; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CaMKII, calcium/calmodulin-dependent protein kinase II; DAG, diacylglycerol; PKD, protein kinase D; HDAC, histone deacetylase; PIP2, phosphatidylinositol-4,5-bisphosphate; IP3, inositol-1,4,5-trisphosphate; IP3R, IP3 receptor; I/R, ischemia/reperfusion; SSH1L, slingshot protein phosphatase 1-like; Bax, Bcl-2 associated X protein; ERK1/2, extracellular signal-regulated kinase 1/2; NF-κB, nuclear factor kappa B; DOX, doxorubicin; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; GSDME, Gasdermin E; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; CaM, calmodulin; MLC, myosin light-chain; MLCK, MLC kinase; PKC, protein kinase C; CPI-17, C-kinase potentiated protein phosphatase 1 inhibitor, molecular mass 17 kDa; MLCP, MLC phosphatase.

Fig. 6. Therapeutic candidate strategies targeting PLCε1. PLCε1, phospholipase C epsilon 1; mAKAP, muscle-specific A-kinase anchoring protein; NP, nanoparticle; miRNA, microRNA; siRNA, small interfering RNA; RISC, RNA-induced silencing complex; DSB, double-strand break; NHEJ: non-homologous end joining; DNMT, DNA methyltransferase.