CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect

Reil, Jan‐Christian; Reil, Gert‐Hinrich; Kov́acs, Árṕad; Sequeira, Vasco; Waddingham, Mark T.; Lódi, Mária; Herwig, Melissa; Ghaderi, Shahrooz; Kreußer, Michael M.; Papp, Zoltán; Voigt, Niels; Dobrev, Dobromir; Meyhöfer, Sebastian M.; Langer, Harald F.; Maier, Lars S.; Linz, Dominik; Mügge, Andreas; Hohl, Mathias; Steendijk, Paul; Hamdani, Nazha

doi:10.1113/jp279607

Cited by 26 publications

(37 citation statements)

References 52 publications

(79 reference statements)

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“…Although the inhibition of CaMKII seems like a promising treatment strategy in CPVT, this strategy might have unappreciated effects on health and disease (Beckendorf et al, 2018 ). This includes hampered cardiac contractile response to exercise training (Burgos et al, 2017 ) and increased afterload (Reil et al, 2020 ), as well as adverse effects in other organs (Beckendorf et al, 2018 ). Thus, increased understanding of how the regulation of CaMKII contributes to the arrhythmogenic phenotype in CPVT might help develop new treatment strategies to prevent arrhythmias, while preserving the physiological effects of CaMKII.…”

Section: Introductionmentioning

confidence: 99%

The oxidation‐resistant CaMKII‐MM281/282VV mutation does not prevent arrhythmias in CPVT1

et al. 2021

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Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased β‐adrenoceptor stimulation‐induced diastolic Ca 2+ leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca 2+ /calmodulin‐dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation‐resistant form of CaMKII protects mice carrying the CPVT1‐causative mutation RyR2‐R2474S (RyR2‐RS) against arrhythmias. Antioxidant treatment (N‐acetyl‐L‐cysteine) reduced the frequency of β‐adrenoceptor stimulation‐induced arrhythmogenic Ca 2+ waves in isolated cardiomyocytes from RyR2‐RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation‐resistant CaMKII‐MM281/282VV variant (MMVV) were crossed with RyR2‐RS mice to create a double transgenic model (RyR2‐RS/MMVV). Wild‐type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2‐RS and RyR2‐RS/MMVV compared to wild‐type mice, both following a β‐adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a β‐adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2‐RS and RyR2‐RS/MMVV mice. Furthermore, no differences were observed in β‐adrenoceptor stimulation‐induced Ca 2+ waves in RyR2‐RS/MMVV compared to RyR2‐RS. In conclusion, antioxidant treatment reduces β‐adrenoceptor stimulation‐induced Ca 2+ waves in RyR2‐RS cardiomyocytes. However, oxidation‐resistant CaMKII‐MM281/282VV does not protect RyR2‐RS mice from β‐adrenoceptor stimulation‐induced Ca 2+ waves or arrhythmias. Hence, alternative oxidation‐sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca 2+ waves in cardiomyocytes from RyR2‐RS mice.

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Section: Introductionmentioning

confidence: 99%

The oxidation‐resistant CaMKII‐MM281/282VV mutation does not prevent arrhythmias in CPVT1

et al. 2021

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“…Recent clinical and experimental data also suggest that cMyBP-C phosphorylation modulates the relative cross-bridge detachment rate with respect to attachment rate and thereby mediates diastolic function [ 55 ]. Previously, we provided evidence on the direct impact of oxidate stress on CaMKII-mediated myofilament protein phosphorylation and function [ 56 ], of which this interaction is likely important in the post-ischemic heart as well. Finally, upstream signaling mechanisms might also show heterogeneity, since interventricular differences were reported in inotropic responses to α 1 -adrenergic stimulation in control mice [ 57 ], as well as in adenylyl cyclase activities in LV MI-induced HF rats [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Interventricular Differences of Signaling Pathways-Mediated Regulation of Cardiomyocyte Function in Response to High Oxidative Stress in the Post-Ischemic Failing Rat Heart

et al. 2021

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Standard heart failure (HF) therapies have failed to improve cardiac function or survival in HF patients with right ventricular (RV) dysfunction suggesting a divergence in the molecular mechanisms of RV vs. left ventricular (LV) failure. Here we aimed to investigate interventricular differences in sarcomeric regulation and function in experimental myocardial infarction (MI)-induced HF with reduced LV ejection fraction (HFrEF). MI was induced by LAD ligation in Sprague–Dawley male rats. Sham-operated animals served as controls. Eight weeks after intervention, post-ischemic HFrEF and Sham animals were euthanized. Heart tissue samples were deep-frozen stored (n = 3–5 heart/group) for ELISA, kinase activity assays, passive stiffness and Ca2+-sensitivity measurements on isolated cardiomyocytes, phospho-specific Western blot, and PAGE of contractile proteins, as well as for collagen gene expressions. Markers of oxidative stress and inflammation showed interventricular differences in post-ischemic rats: TGF-β1, lipid peroxidation, and 3-nitrotyrosine levels were higher in the LV than RV, while hydrogen peroxide, VCAM-1, TNFα, and TGF-β1 were increased in both ventricles. In addition, nitric oxide (NO) level was significantly decreased, while FN-1 level was significantly increased only in the LV, but both were unchanged in RV. CaMKII activity showed an 81.6% increase in the LV, in contrast to a 38.6% decrease in the RV of HFrEF rats. Cardiomyocyte passive stiffness was higher in the HFrEF compared to the Sham group as evident from significantly steeper Fpassive vs. sarcomere length relationships. In vitro treatment with CaMKIIδ, however, restored cardiomyocyte passive stiffness only in the HFrEF RV, but had no effect in the HFrEF LV. PKG activity was lower in both ventricles in the HFrEF compared to the Sham group. In vitro PKG administration decreased HFrEF cardiomyocyte passive stiffness; however, the effect was more pronounced in the HFrEF LV than HFrEF RV. In line with this, we observed distinct changes of titin site-specific phosphorylation in the RV vs. LV of post-ischemic rats, which may explain divergent cardiomyocyte stiffness modulation observed. Finally, Ca2+-sensitivity of RV cardiomyocytes was unchanged, while LV cardiomyocytes showed increased Ca2+-sensitivity in the HFrEF group. This could be explained by decreased Ser-282 phosphorylation of cMyBP-C by 44.5% in the RV, but without any alteration in the LV, while Ser-23/24 phosphorylation of cTnI was decreased in both ventricles in the HFrEF vs. the Sham group. Our data pointed to distinct signaling pathways-mediated phosphorylations of sarcomeric proteins for the RV and LV of the post-ischemic failing rat heart. These results implicate divergent responses for oxidative stress and open a new avenue in targeting the RV independently of the LV.

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“…Of those, the γ and δ isoforms are predominantly expressed in the heart. In addition, CaMKII activity is primarily regulated by four posttranslational modifications, including the Ca 2+ /calmodulin-binding, autophosphorylation [43,44], oxidation [45], O-linked N-acetylglucosamination (O-GlcNAc) [46], and S-nitrosylation [47] of CaMKII. Several studies have confirmed that the sustained activation of CaMKII modulates potassium channels [48], whereas the inhibition of CaMKII may prevent the internalization of K ATP channels caused by ischemia, thereby reducing the vulnerability of CMs to injury [49,50].…”

Section: Discussionmentioning

confidence: 99%

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

Cheng

Sun

et al. 2020

Lipids Health Dis

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Background: Cardiac Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activation plays a critical role in cardiomyocyte (CM) apoptosis and arrhythmia. Functional ATP-sensitive potassium (K ATP) channels are essential for cardiac protection during ischemia. In cultured CMs, L5 low-density lipoprotein (LDL) induces apoptosis and QTc prolongation. L5 is a highly electronegative and atherogenic aberrant form of LDL, and its levels are significantly higher in patients with cardiovascular-related diseases. Here, the role of L5 in cardiac injury was studied by evaluating the effects of L5 on CaMKII activity and K ATP channel physiology in CMs. Methods: Cultured neonatal rat CMs (NRCMs) were treated with a moderate concentration (ie, 7.5 μg/mL) of L5 or L1 (the least electronegative LDL subfraction). NRCMs were examined for apoptosis and viability, CaMKII activity, and the expression of phosphorylated CaMKIIδ and NOX2/gp91 phox. The function of K ATP and action potentials (APs) was analyzed by using the patch-clamp technique. Results: In NRCMs, L5 but not L1 significantly induced cell apoptosis and reduced cell viability. Furthermore, L5 decreased Kir6.2 expression by more than 50%. Patch-clamp analysis showed that L5 reduced the K ATP current (I KATP) density induced by pinacidil, a K ATP opener. The partial recovery of the inward potassium current during pinacidil washout was susceptible to subsequent inhibition by the I KATP blocker glibenclamide. Suppression of I KATP by L5 significantly prolonged the AP duration. L5 also significantly increased the activity of CaMKII, the phosphorylation of CaMKIIδ, and the expression of NOX2/gp91 phox. L5-induced apoptosis was prevented by the addition of the CaMKII inhibitor KN93 and the reactive oxygen species scavenger Mn (III)TBAP. Conclusions: L5 but not L1 induces CM damage through the activation of the CaMKII pathway and increases arrhythmogenicity in CMs by modulating the AP duration. These results help to explain the harmful effects of L5 in cardiovascular-related disease.

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CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect

Cited by 26 publications

References 52 publications

The oxidation‐resistant CaMKII‐MM281/282VV mutation does not prevent arrhythmias in CPVT1

The oxidation‐resistant CaMKII‐MM281/282VV mutation does not prevent arrhythmias in CPVT1

Interventricular Differences of Signaling Pathways-Mediated Regulation of Cardiomyocyte Function in Response to High Oxidative Stress in the Post-Ischemic Failing Rat Heart

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

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