CaMK4 Gene Deletion Induces Hypertension

Overview

Journal J Am Heart Assoc

Specialty Cardiology & Vascular Diseases

Date 2012 Nov 7

PMID 23130158

Citations 113

Authors

Gaetano Santulli

Ersilia Cipolletta

Daniela Sorriento

Carmine Del Giudice

Antonio Anastasio

Sara Monaco

Angela Serena Maione

Gianluigi Condorelli

Annibale Puca

Bruno Trimarco

Maddalena Illario

Guido Iaccarino

Affiliations

Soon will be listed here.

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.).

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References

Miyano O, Kameshita I, Fujisawa H . Purification and characterization of a brain-specific multifunctional calmodulin-dependent protein kinase from rat cerebellum. J Biol Chem. 1992; 267(2):1198-203. View

Iaccarino G, Keys J, Rapacciuolo A, Shotwell K, Lefkowitz R, Rockman H . Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors. J Am Coll Cardiol. 2001; 38(2):534-40. DOI: 10.1016/s0735-1097(01)01396-1. View

Passier R, Zeng H, Frey N, Naya F, Nicol R, McKinsey T . CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest. 2000; 105(10):1395-406. PMC: 315462. DOI: 10.1172/JCI8551. View

Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G . Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo. Hypertension. 2012; 60(1):129-36. DOI: 10.1161/HYPERTENSIONAHA.111.189605. View

Jin H, Chemaly E, Lee A, Kho C, Hadri L, Hajjar R . Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy. FASEB J. 2009; 24(2):451-63. PMC: 2812033. DOI: 10.1096/fj.09-136622. View

Gadano A, Sogni P, Yang S, Cailmail S, Moreau R, NEPVEUX P . Endothelial calcium-calmodulin dependent nitric oxide synthase in the in vitro vascular hyporeactivity of portal hypertensive rats. J Hepatol. 1997; 26(3):678-86. DOI: 10.1016/s0168-8278(97)80435-7. View

Santulli G, Lombardi A, Sorriento D, Anastasio A, Del Giudice C, Formisano P . Age-related impairment in insulin release: the essential role of β(2)-adrenergic receptor. Diabetes. 2012; 61(3):692-701. PMC: 3282797. DOI: 10.2337/db11-1027. View

Perino A, Ghigo A, Ferrero E, Morello F, Santulli G, Baillie G . Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ. Mol Cell. 2011; 42(1):84-95. PMC: 3265115. DOI: 10.1016/j.molcel.2011.01.030. View

Donaldson C, Eder S, Baker C, Aronovitz M, Weiss A, Hall-Porter M . Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. Circ Res. 2008; 104(2):265-75, 11p following 275. PMC: 4427027. DOI: 10.1161/CIRCRESAHA.108.190397. View

10.

Santulli G . Coronary heart disease risk factors and mortality. JAMA. 2012; 307(11):1137. DOI: 10.1001/jama.2012.323. View

11.

Kilander L, Nyman H, Boberg M, Hansson L, Lithell H . Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998; 31(3):780-6. DOI: 10.1161/01.hyp.31.3.780. View

12.

Knoll R, Iaccarino G, Tarone G, Hilfiker-Kleiner D, Bauersachs J, Leite-Moreira A . Towards a re-definition of 'cardiac hypertrophy' through a rational characterization of left ventricular phenotypes: a position paper of the Working Group 'Myocardial Function' of the ESC. Eur J Heart Fail. 2011; 13(8):811-9. DOI: 10.1093/eurjhf/hfr071. View

13.

Bok J, Wang Q, Huang J, Green S . CaMKII and CaMKIV mediate distinct prosurvival signaling pathways in response to depolarization in neurons. Mol Cell Neurosci. 2007; 36(1):13-26. PMC: 2040167. DOI: 10.1016/j.mcn.2007.05.008. View

14.

Lanni F, Santulli G, Izzo R, Rubattu S, Zanda B, Volpe M . The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients. J Hypertens. 2007; 25(3):551-6. DOI: 10.1097/HJH.0b013e328013cd67. View

15.

Sorriento D, Santulli G, Fusco A, Anastasio A, Trimarco B, Iaccarino G . Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-kappaB-dependent hypertrophic gene expression. Hypertension. 2010; 56(4):696-704. DOI: 10.1161/HYPERTENSIONAHA.110.155960. View

16.

Ho N, Liauw J, Blaeser F, Wei F, Hanissian S, Muglia L . Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J Neurosci. 2000; 20(17):6459-72. PMC: 6772951. View

17.

Ribar T, Rodriguiz R, Khiroug L, Wetsel W, Augustine G, Means A . Cerebellar defects in Ca2+/calmodulin kinase IV-deficient mice. J Neurosci. 2000; 20(22):RC107. PMC: 6773177. View

18.

You J, Peng W, Lin X, Huang Q, Lin J . PLC/CAMK IV-NF-kappaB involved in the receptor for advanced glycation end products mediated signaling pathway in human endothelial cells. Mol Cell Endocrinol. 2010; 320(1-2):111-7. DOI: 10.1016/j.mce.2010.01.036. View

19.

Wagner S, Ruff H, Weber S, Bellmann S, Sowa T, Schulte T . Reactive oxygen species-activated Ca/calmodulin kinase IIδ is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res. 2011; 108(5):555-65. PMC: 3065330. DOI: 10.1161/CIRCRESAHA.110.221911. View

20.

De Backer G, Germano G, Grassi G, Ruilope L, Rynkiewicz A, Boudier H . 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). Eur Heart J. 2007; 28(12):1462-536. DOI: 10.1093/eurheartj/ehm236. View