Coordinate Changes in Myosin Heavy Chain Isoform Gene Expression Are Selectively Associated With Alterations in Dilated Cardiomyopathy Phenotype

Abraham, William T.; Gilbert, Edward M.; Lowes, Brian D.; Minobe, Wayne; Larrabee, Patricia S.; Roden, Robert L.; Dutcher, Darrin; Sederberg, James; Lindenfeld, Jo Ann; Wolfel, Eugene E.; Shakar, Simon F.; Ferguson, Debra A.; Volkman, Kirk; Linseman, Jennifer V.; Quaife, Robert A.; Robertson, Alastair D.; Bristow, Michael R.

doi:10.1007/bf03402039

Cited by 94 publications

(71 citation statements)

References 38 publications

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“…For example, the expression of MHCs reflects compensatory mechanisms under increased myocardial load (17) as well as in manifest cardiomyopathy (18). Compared with α-MHC, β-MHC is considered as the MHC isoform with a higher degree of efficiency (19).…”

Section: Discussionmentioning

confidence: 99%

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

et al. 2014

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Background: Intrauterine growth restriction (IUGR) is an important risk factor for cardiovascular disease. Previous studies revealed altered myocardial matrix composition after IUGR. We hypothesized that IUGR is accompanied by compromised myocardial performance independently from arterial hypertension. Methods: IUGR was induced in Wistar rats by maternal protein restriction, and hearts of male offspring were studied using echocardiography, immunohistochemistry, real-time PCR, and western blot analysis. results: At day 70 of life, in the absence of arterial hypertension (mean arterial blood pressure: 101.3 ± 7.1 mmHg in IUGR vs. 105.3 ± 4.6 mmHg in controls, not significant (NS)), echocardiography showed a reduced contractility (ejection fraction: 65.4 ± 1.8% in IUGR vs. 82.2 ± 1.5% in controls, P < 0.001) of a more distensible myocardium in IUGR rats. Altered expression patterns of myosin chains and titin isoforms and increased expression levels of atrial natriuretic peptide, Na/K-ATPase, and β-adrenergic receptor 1 were detected. A higher number of cardiac fibroblasts and vascular cross-sections were observed in IUGR rats, accompanied by elevated expression of hypoxia inducible factor 1 target genes, such as vascular endothelial growth factor and its receptors. conclusion: We observed a blood pressure-independent impairment of myocardial function after IUGR, which possibly favors cardiovascular disease later in life. Some IUGR-induced myocardial changes (e.g., sarcomeric components) may partly explain the compromised cardiac performance, whereas others (e.g., elevated vascular supply) reflect compensatory mechanisms.

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Section: Discussionmentioning

confidence: 99%

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

et al. 2014

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“…In patients who respond to either metoprolol or carvedilol by improving their LVEF by at least 5 EF units, the baseline downregulated mRNA for the high myosin ATPase, adult ␣-isoform of myosin heavy chain increases toward the normal range in the human heart, and the low ATPase activity ␤-, "fetal" isoform downregulates. 115,172 In addition, mRNA expression of sarcoplasmic reticulum Ca 2ϩ ATPase (Serca2a), often included as an adult gene in the FGP, upregulates into the normal range in LVEF responders but decreases in nonresponders. 115 At the protein level these changes in MyHC isoforms and Serca2a would be expected to improve contractile function.…”

Section: Mechanism Of Action Of ␤-Blockers Inmentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

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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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“…In the normal adult myocardium, only basal MEF2 activity is required for the maintenance of contractile properties, whereas stress stimuli, through MAPK, stimulate its activity (Figure 2) (91,92). In the adult, these factors induce a fetal gene program, which might be beneficial in adapting to stress, in principle, but then leads to altered contractility, uncontrolled calcium transients and inadequate energetic and, finally, maladaptative changes (93)(94)(95).…”

Section: Cooperative Effects On the Ras Pathway: Cross-links In Hypermentioning

confidence: 99%

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Sala

Gallo

Leo

et al. 2012

Mol Med

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Coordinate Changes in Myosin Heavy Chain Isoform Gene Expression Are Selectively Associated With Alterations in Dilated Cardiomyopathy Phenotype

Cited by 94 publications

References 38 publications

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

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