CaKMII Inhibition in Obese, Diabetic Mice leads to Lower Blood Glucose Levels
Reporter: Larry H Bernstein, MD, FCAP
This recent publication was reported in MedPage today. It is different than, but highly suggestive of our recent report about the Univesity of Iowa discovery of “Oxidized CaKMII inhibition” as a therapeutic target for atrial arrhythmia.
http://pharmaceuticalintelligence.com/2013/10/26/oxidized-calcium-calmodulin-kinase-and-atrial-fibrillation/
- Ang II infusion increased the susceptibility of mice to AF induction by rapid right atrial pacing and established a framework for us to test the hypothesized role of ox-CaMKII in promoting AF. ox-CaMKII is critical for AF.
- Established a critical role of ox-CaMKII in promoting AF
- Ang II induced increases in ROS production seen in WT atria were absent in atria from MsrA TG mice suggesting that MsrA sensitive targets represent an important component of Ang II mediated atrial oxidation.
- The protection from AF in MsrA TG mice appeared to be independent of pressor effects that are critical for the proarrhythmic actions.
- These findings suggest that NADPH oxidase dependent ROS and elevated ox-CaMKII
- drive Ang II -pacing-induced AF and that
- targeted antioxidant therapy, by MsrA over-expression,
- can reduce or prevent AF in Ang -II-infused mice.
- is associated with an increased susceptibility to acquired arrhythmias, including AF
- require access to RyR2 serine 2814.
- these mice were not resistant to the hemodynamic effects of Ang II, but were nevertheless protected from AF.
- sinus node dysfunction and AF are downstream consequences of elevated ox-CaMKII.
- Contributions to cardiomyocyte interactions and signaling
Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/10/21/contributions-to-cardiomyocyte-interactions-and-signaling/ - Cardiac Contractility & Myocardium Performance: Therapeutic Implications for Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Editor: Justin Pearlman, MD, PhD, FACC, Author and Curator: Larry H Bernstein, MD, FCAP, and Article Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/ - Part I. Identification of Biomarkers that are Related to the Actin Cytoskeleton
Curator and Writer: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/ - Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility
Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/ - Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/ - Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD
Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/ - Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/ - Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/ - Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/ - Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/ - Genetic Analysis of Atrial Fibrillation
Author and Curator: Larry H Bernstein, MD, FCAP , and Curator: Aviva-Lev Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/10/27/genetic-analysis-of-atrial-fibrillation/
Diabetes: Mouse Studies Point to Kinase as Treatment Target
- knocked out downstream processes, including p38 and MAPK-activating protein kinase 2 (MK2).
- improved insulin-induced Akt-phosphorylation in obese mice —
- an important part of improving insulin sensitivity.
- these changes didn’t occur through effects on FoxO1.
- suppression of ATF4 — all of which led to an
- increase in Akt-phosphorylation and insulin sensitivity.
- the suppression of TRB3 by CaKMII deficiency is
- causally important in the improvement in insulin signaling,
- one involved in CaKMII-p38-FoxO1 dependent hepatic glucose production, and
- the other involved in defective insulin-induced p-Akt,
- both hyperglycemia and insulin resistance in type 2 diabetes
- an allosteric version that will more specifically target MK2
- by binding to a site that is unique to this enzyme.
- when you inhibit p38 by that mechanism, mainly by inhibiting MK2,
- you avoid the adverse effects,
- CaKMII inhibitors are in development for heart failure and
- MK2 inhibitors are being looked at as an alternative to p38 inhibitors for inflammatory diseases.
- CaKMII is generally overactive in obese patients
- who have not yet progressed to full blown diabetes, but is not overactive in lean people.
- they have the hallmarks that they’re going to get diabetes.”