CaMKII and a failing strategy for growth in heart

Anderson, Mark E.

doi:10.1172/jci39262

Cited by 57 publications

(53 citation statements)

References 26 publications

(25 reference statements)

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“…Mice overexpressing an activated mutant calcineurin showed an increase in heart size, geometrical disorganization and extensive collagen deposition (35). Another kinase pathway involves Ca 2+ /calmodulindependent kinase II (CaMKII), reflected by its expression and activity are enhanced in HF (36). Rats overexpressing CaMKII showed chamber dilation, myocyte enlargement and high levels of fibrosis (37).…”

Section: Ros and Cardiac Hypertrophy Signallingmentioning

confidence: 99%

Cardiac remodelling: General aspects and mechanisms

Pontes¹,

Pontes²

2016

Curr Res Cardiol

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Section: Ros and Cardiac Hypertrophy Signallingmentioning

confidence: 99%

Cardiac remodelling: General aspects and mechanisms

Pontes¹,

Pontes²

2016

Curr Res Cardiol

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“…Therefore, we were unable to determine which site is phosphorylated by CaMKII leading to the subsequent reduced amount of HDAC 4 protein in hearts of the LBW lambs. However, CaMKII and HDAC 4 protein have been associated with cardiac pathology in human and animal models of cardiac hypertrophy (2,28,33,58) and heart failure with an upregulation of CaMKII expression (29,61).…”

Section: Igf-2r Increased G ␣Q Signaling But Not G ␣S Signaling In Tmentioning

confidence: 99%

IGF-2R-G_αqsignaling and cardiac hypertrophy in the low-birth-weight lamb

Wang

Tosh

Zhang

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving ␣q (G␣q) or ␣s (G␣s). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in lowbirth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phosphoCaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate G ␣q signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life. low birth weight; insulin-like growth factor 2 receptor; histone acetylation

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“…129 On balance, as depicted in Figure 6, the ␤ 1 -AR/CaMKII signaling is adverse and is one of the ways in which CaMKII signaling can play an adverse role in the failing heart by promoting pathological hypertrophy and arrhythmias. 130,131 On the other hand, PKA-dependent signaling can be beneficial, as evidenced by the remodeling prevention effects of overexpression of Type VI adenylyl cyclase, 132 the cardiomyopathic effects of CREB genetic inhibition, 133 and the antihypertrophic effects of PKA on Class II histone deacetylases. 134 To be sure, PKA-mediated signaling can also be adverse, both on the myocardium 135 and in promoting arrhythmias, 136 but, as depicted in Figure 6, PKA signaling has elements of both benefit and harm and encompasses most of the upside effects of ␤-adrenergic activation.…”

Section: Pka-dependent and Pka-independent Signalingmentioning

confidence: 99%

“…The failed attempts to improve on ␤-blocker therapy include the use of compounds with ISA in isolated or intact human heart, 110,179 the addition of PDE3 inhibitors, 122,124 the use of ␤-blockers with ␤ 3 -agonist activity, 79,80 and the use of pure sympatholytic agents. 180 As-yet untested possible new approaches are the addition of a ␤ 2 -agonist to a ␤ 1 -blocker, 109 the use of pharmacogenetics to modulate the effects of sympatholytics into a more ideal, mild NE-lowering range, 116 CaMKII inhibition 130,131 added to ␤-blockade, the addition to ␤-blockade of agents that dephosphorylate receptors and restore receptor function, 146,147 and prospective pharmacogenetic targeting of ␤-blockers that distinguish between different genetic variants of ␤ 1 -ARs. 116,117,163 Although it is likely that one or more of these approaches will be successful, the fact that it has proved difficult to improve on single agent ␤-blockade is a powerful testament to the effectiveness of this form of heart failure therapy.…”

Section: Can Antiadrenergic Therapy Be Improvedmentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

151

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ReviewTranslational Success Stories highlight how basic discoveries have led to clinical advances (such as the use of new drugs or diagnostic modalities in patients). This initiative reflects the renewed emphasis of our journal on translational research. It is hoped that these articles will stimulate efforts to translate basic insights into clinical practice. Treatment of Chronic Heart Failure With ␤-AdrenergicReceptor Antagonists A Convergence of Receptor Pharmacology and Clinical CardiologyMichael R. BristowAbstract: Despite the absence of a systematic development plan, ␤-blockers have reached the top tier of medical therapies for chronic heart failure. The successful outcome was due to the many dedicated investigators who produced, over a 30-year period, increasing evidence that ␤-blocking agents should or actually did improve the natural history of dilated cardiomyopathies and heart failure. It took 20 years for supportive evidence to become undeniable, at which time in 1993 the formidable drug development resources of large pharmaceutical companies were deployed into Phase 3 trials. Success then came relatively quickly, and within 8 years multiple agents were on the market in the United States and Europe. Importantly, there is ample room to improve antiadrenergic therapy, through novel approaches exploiting the nuances of receptor biology and/or intracellular signaling, as well as through pharmacogenetic targeting. (Circ Res. 2011;109:1176-1194.)Key Words: heart failure Ⅲ adrenergic receptors Ⅲ ␤-blockers Ⅲ norepinephrine Ⅲ drug development "I love it when a plan comes together" -Colonel John "Hannibal" Smith, The A-Team ␤ -Adrenergic blocking agents are now considered firstline therapy for chronic heart failure. 2 Between 1971 and 2001, ␤-blockers as a drug class went from contraindicated to being universally declared a highly effective new therapy for chronic heart failure with systolic dysfunction. As depicted in Figure 1, this 180-degree turn required the convergence of initially disconnected lines of basic and clinical investigation, none of which was systematically planned by the usual purveyors of drug development, large pharmaceutical companies. However, as for the typical outcome of Colonel Hannibal Smith's unconventional and dubious tactical schemes, 1 the end result was highly successful. This review provides some of the historical highlights, summarizes current knowledge, and provides thoughts on the future of ␤-blocker and antiadrenergic therapy. Historical Highlights Discovery of Adrenergic ReceptorsIn 1948, Raymond Ahlquist reported evidence for two types of adrenergic receptors, 3 which, "for convenience," he termed alpha and beta. The evidence was based on 2 distinct rank orders of agonist potency for a variety of pharmacological responses, plus the ability to inhibit the vasoconstrictor or uterine contraction responses of the ␣ group, with 3 different compounds (dibenamine, ergotoxine, or tolazoline) that would later be termed ␣-blocking agents. At the time of Ahlquist's landmark work, the...

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CaMKII and a failing strategy for growth in heart

Cited by 57 publications

References 26 publications

Cardiac remodelling: General aspects and mechanisms

Cardiac remodelling: General aspects and mechanisms

IGF-2R-G_αqsignaling and cardiac hypertrophy in the low-birth-weight lamb

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

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CaMKII and a failing strategy for growth in heart

Cited by 57 publications

References 26 publications

Cardiac remodelling: General aspects and mechanisms

Cardiac remodelling: General aspects and mechanisms

IGF-2R-Gαqsignaling and cardiac hypertrophy in the low-birth-weight lamb

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

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IGF-2R-G_αqsignaling and cardiac hypertrophy in the low-birth-weight lamb