For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
86
views
42
references
 Top references
cited by
93
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      563
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      CaMK4 Gene Deletion Induces Hypertension

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          The expression of calcium/calmodulin-dependent kinase IV (CaMKIV) was hitherto thought to be confined to the nervous system. However, a recent genome-wide analysis indicated an association between hypertension and a single-nucleotide polymorphism (rs10491334) of the human CaMKIV gene ( CaMK4 ), which suggests a role for this kinase in the regulation of vascular tone.

          Methods and Results

          To directly assess the role of CaMKIV in hypertension, we characterized the cardiovascular phenotype of CaMK4 −/− mice. They displayed a typical hypertensive phenotype, including high blood pressure levels, cardiac hypertrophy, vascular and kidney damage, and reduced tolerance to chronic ischemia and myocardial infarction compared with wild-type littermates. Interestingly, in vitro experiments showed the ability of this kinase to activate endothelial nitric oxide synthase. Eventually, in a population study, we found that the rs10491334 variant associates with a reduction in the expression levels of CaMKIV in lymphocytes from hypertensive patients.

          Conclusions

          Taken together, our results provide evidence that CaMKIV plays a pivotal role in blood pressure regulation through the control of endothelial nitric oxide synthase activity. ( J Am Heart Assoc. 2012;1:e001081 doi: 10.1161/JAHA.112.001081.)

          Related collections

          Most cited references42

          • Record: found
          • Abstract: not found
          • Article: not found

          2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

          G. Mancia, G. De Backer, A. Dominiczak … (2006)
          Article 0 comments Cited 324 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Hypertension in mice lacking the gene for endothelial nitric oxide synthase.

            P L Huang, Z. Huang, H Mashimo … (1995)
            Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
            Article 0 comments Cited 302 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Reactive oxygen species-activated Ca/calmodulin kinase IIδ is required for late I(Na) augmentation leading to cellular Na and Ca overload.

              Caroline S. Wagner, Megan Weber, H Ruff … (2011)
              In heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late I(Na) leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation. We tested whether CaMKIIδ is required for ROS-dependent late I(Na) regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved. 40 μmol/L H(2)O(2) significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free [Ca](i) (5 mmol/L BAPTA/1 mmol/L Br(2)-BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 μmol/L), the H(2)O(2)-dependent CaMKII oxidation and autophosphorylation was abolished. H(2)O(2) significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H(2)O(2) increased late I(Na) (whole cell patch-clamp). This increase was abolished in CaMKIIδ(-/-) myocytes. H(2)O(2)-induced [Na](i) and [Ca](i) accumulation (SBFI [sodium-binding benzofuran isophthalate] and Indo-1 epifluorescence) was significantly slowed in CaMKIIδ(-/-) myocytes (versus WT). CaMKIIδ(-/-) myocytes developed significantly less H(2)O(2)-induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late I(Na), [Na](i) and [Ca](i) accumulation) were obtained by overexpression of CaMKIIδ in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 μmol/L KN93 or 0.1 μmol/L AIP [autocamtide 2-related inhibitory peptide]). Free [Ca](i) and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIδ enhances late I(Na), which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression.
              Article 0 comments Cited 84 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): J Am Heart Assoc
                Journal ID (iso-abbrev): J Am Heart Assoc
                Journal ID (hwp): ahaoa
                Journal ID (publisher-id): jah3
                Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Electronic): 2047-9980
                Publication date Collection: August 2012
                Publication date (Electronic): 24 August 2012
                Volume: 1
                Issue: 4
                Electronic Location Identifier: e001081
                Affiliations
                Department of Clinical Medicine, Cardiovascular and Immunologic Sciences, “Federico II” University of Naples, Naples, Italy (G.S., E.C., D.S., C.D.G., A.A., B.T.)
                Department of Cellular and Molecular Biology and Pathology, “Federico II” University of Naples, Naples, Italy (S.M., A.S.M., M.I.)
                Istituto clinico Humanitas IRCCS and Istituto Ricerca Genetica Biomedica, National Research Council, Rozzano, Italy (G.C.)
                Multimedica Research Hospital, Milan, Italy (G.C., A.P., G.I.)
                Department of Medicine and Surgery, University of Salerno, Salerno, Italy (A.P., G.I.)
                Author notes
                Correspondence to: Guido Iaccarino, MD, PhD, FESC, Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081 Baronissi (Salerno), Italy. E-mail giaccarino@ 123456unisa.it
                Article
                Publisher ID: jah359
                DOI: 10.1161/JAHA.112.001081
                PMC ID: 3487344
                PubMed ID: 23130158
                SO-VID: b4b95d4a-bba4-4622-9886-5e58e8346053
                Copyright © © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell.
                License:

                This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 17 April 2012
                Date accepted : 21 June 2012
                Categories
                Subject: Original Research
                Subject: Hypertension

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: angiogenesis,hypertrophy,hypertension,arrhythmia,endothelium
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: angiogenesis, hypertrophy, hypertension, arrhythmia, endothelium

                Comments

                Comment on this article

                scite_

                Similar content563

                See all similar

                Cited by91

                See all cited by

                Most referenced authors892

                See all reference authors