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IP3 receptor orchestrates maladaptive vascular responses in heart failure
Haikel Dridi, … , Alain Lacampagne, Andrew R. Marks
Haikel Dridi, … , Alain Lacampagne, Andrew R. Marks
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e152859. https://doi.org/10.1172/JCI152859.
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Research Article Cardiology Cell biology

IP3 receptor orchestrates maladaptive vascular responses in heart failure

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Abstract

Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC–/– mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC–/– mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC–/– mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC–/– mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.

Authors

Haikel Dridi, Gaetano Santulli, Jessica Gambardella, Stanislovas S. Jankauskas, Qi Yuan, Jingyi Yang, Steven Reiken, Xujun Wang, Anetta Wronska, Xiaoping Liu, Alain Lacampagne, Andrew R. Marks

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Figure 6

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

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IP3R1 in vascular smooth muscle mediates increased vascular tone during ...
ATII binds to GPCRs (Gq–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.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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