Myocardial Gene Expression in Dilated Cardiomyopathy Treated with Beta-Blocking Agents

Lowes, Brian D.; Gilbert, Edward M.; Abraham, William T.; Minobe, Wayne; Larrabee, Patricia S.; Ferguson, Debra A.; Wolfel, Eugene E.; Lindenfeld, Jo Ann; Tsvetkova, Tatiana; Robertson, Alastair D.; Quaife, Robert A.; Bristow, Michael R.

doi:10.1056/nejmoa012630

Cited by 460 publications

(349 citation statements)

References 24 publications

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“…The MHC isozyme switch from the fast type α isoform to the slow type β isoform (lower ratio of MHC-α to MHC-β) is believed to play a significant role in cardiac dysfunction in diabetes, cardiac hypertrophy and senescence [28,29,49,50]. This is supported by the fact that an increase in MHC-α and a decrease in MHC-β mRNA expression (increased ratio of MHC-α to MHC-β) is deemed beneficial in the improvement of left ventricular function in patients with idiopathic dilated cardiomyopathy [31]. Similarly, our results reveal a significant isozyme switch from MHC-α to MHC-β in Lep/Lep mice, which may contribute to contractile dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…An altered distribution of MHC isoforms has been shown in myocardial remodelling, cardiac hypertrophy and cardiomyopathy [17,[28][29][30][31], indicating that the regulation of cardiac contractile function is directly related to the relative amounts of MHC-α and MHC-β isozymes [25]. Even a small shift in the relative expression of these isoforms may significantly alter cardiomyocyte power output [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Even a small shift in the relative expression of these isoforms may significantly alter cardiomyocyte power output [30,31]. Although the predominant MHC isoform in healthy human hearts is β rather than α, overexpression of MHC-β in transgenic mice suggests that such an MHC-α to MHC-β switch is a maladaptive response to preserve energy [30].…”

Section: Discussionmentioning

confidence: 99%

“…5b,c). It has been reported that expression of MHC isozymes is associated with cardiac function, especially in myocardial remodelling and cardiomyopathies [17,[28][29][30][31]. We examined the pattern of MHC isozyme distribution in Lep/Lep heart.…”

Section: Mechanical Properties Of Cardiomyocytesmentioning

confidence: 99%

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Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

et al. 2006

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Aims/hypothesis: Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo) plasmic reticulum Ca 2+ -ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice. Methods: Mechanical properties were evaluated in ventricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR 50 , TR 90 ), maximal velocity of shortening/relengthening (±dL/dt), intracellular Ca 2+ and its decay (τ). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and 45 Ca 2+ uptake, respectively. NADPH oxidase was determined by immunoblotting. Results: Myocytes from Lep/Lep mice displayed depressed PS and ± dL/dt, prolonged TR 50 , TR 90 , elevated resting [Ca 2+ ] i , prolonged τ, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca 2+ compared with lean controls. Cardiac glutathione/glutathione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47 phox and membrane gp91 phox were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/ Lep hearts and associated with decreased 45 Ca 2+ uptake. The MHC isozyme displayed a shift from the α to the β isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and 45 Ca 2+ uptake seen in Lep/ Lep myocytes. Incubation of the NADPH oxidase inhibitor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity. Conclusions/interpretation: These data indicate that obesity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mechanical Properties Of Cardiomyocytesmentioning

confidence: 99%

See 2 more Smart Citations

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

et al. 2006

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“…However, there was no shift in the EC 50 (b), indicating that the affinity of the receptor to angiotensin II was unaltered. *p<0.05 vs non-diabetic myocardium blood pressure and their medical treatment with beta blockers and statins, since all of these factors may influence gene expression [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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Aims/hypothesis The angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin-angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients. Methods Gene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II. Results Diabetic myocardium showed a significant increase in protein expression (170±16% of control) and median mRNA expression (186% of control) of the AT1 receptor.The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89±5.5% vs 29±1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression. Conclusions/interpretation AT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients.

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The Fear of β-Blocker Therapy in Heart Failure

Chatterjee¹

2004

Arch Intern Med

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Myocardial Gene Expression in Dilated Cardiomyopathy Treated with Beta-Blocking Agents

Abstract: In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.

Cited by 460 publications

References 24 publications

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

The Fear of β-Blocker Therapy in Heart Failure

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