Figure 6. IP3R1 in vascular smooth muscle mediates increased vascular tone during HF.

ATII binds to GPCRs (G_q–G₁₁) and activates PLC, which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), resulting in 2 second messengers: IP3 and diacylglycerol (DAG). IP3 binds to its receptor IP3R1 on the SR, causing Ca²⁺ release into the cytosol. Furthermore, increased catecholamines during HF bind to adrenergic (AD) receptors and activate the Gs protein and AC, leading to increased levels of cAMP. cAMP activates PKA, which phosphorylate the IP3R1 channels, causing further Ca²⁺ release into the cytosol. IP3R1 binds AKAP9, which anchors a pool of PKA to the channel. Of note, PKA phosphorylates RyR2 and SR/ER Ca²⁺-ATPase type 2 (SERCA2a), which play a role in SR Ca²⁺ release and uptake processes, respectively. An increase in the cytosolic Ca²⁺ concentration activates the CAM protein. CAM activates MLCK, which in turn phosphorylates MLC20, leading to smooth muscle contraction and vasoconstriction. Chronic vasoconstriction increases cardiac afterload, thereby promoting decompensated HF. Both genetic depletion of VSMC IP3R1 and pharmacologic inhibition of MLCK with ML-7 attenuate MLCK activation and phosphorylation of MLC20, thus reducing vasoconstriction and cardiac afterload in failing hearts. MLCP, myosin light chain phosphatase; PLN, phospholamban.