Myosin heavy chain gene expression in human heart failure.

Nakao, Kōichi; Minobe, Wayne; Roden, Robert L.; Bristow, Michael R.; Leinwand, Leslie A.

doi:10.1172/jci119776

Cited by 365 publications

(294 citation statements)

References 42 publications

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“…Although this mechanism plays an important role in regulation of contractile activity of the rodent's heart, its value in the control of the heart function of large mammals remains disputed because they express mainly one isoform, ␤-MHC (11). In the human heart, 2-7% ␣-MHC expression has been reported, but its distribution in the myocardium is not yet known (28). In rodent hearts, the ␣-to ␤-MHC ratio is ϳ95:5, which is nearly opposite to the human isoform ratio.…”

Section: Preparation Numbermentioning

confidence: 95%

HDAC3-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

Samant¹,

Courson²,

Sundaresan³

et al. 2011

Journal of Biological Chemistry

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Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II histone deacetylase (HDAC), HDAC4, and a histone acetyltransferase, PCAF, associate with cardiac sarcomeres, and a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study, we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres. By immunohistochemical and electron microscopic analyses, we found that HDAC3 was localized to the A band of sarcomeres and was capable of deacetylating myosin heavy chain (MHC) isoforms. The motor domains of both cardiac ␣-and ␤-MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the K m for the actin-activated ATPase activity of both ␣-and ␤-MHC isoforms. By an in vitro motility assay, we found that lysine acetylation increased the actin sliding velocity of ␣-myosin by 20% and ␤-myosin by 36%, compared to their respective non-acetylated isoforms. Moreover, myosin acetylation was found to be sensitive to cardiac stress. During induction of hypertrophy, myosin isoform acetylation increased progressively with duration of stress stimuli, independent of isoform shift, suggesting that lysine acetylation of myosin could be an early response of myofilaments to increase contractile performance of the heart. These studies provide the first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms.

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Section: Preparation Numbermentioning

confidence: 95%

HDAC3-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

Samant¹,

Courson²,

Sundaresan³

et al. 2011

Journal of Biological Chemistry

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“…In contrast to ANF and BNP, however, β-MHC up-regulation was not observed at 4 wk and was instead significantly reactivated only at 8 and 12 wk, stages associated with dilation remodeling and increased mortality risk. This suggests that an altered α-/β-MHC ratio, known to detrimentally affect adult cardiac function in both mice and humans (25), was aligned most closely with phenotype progression in Prox1 adult mutant mice. Expression profiling of β-MHC additionally revealed correct postnatal down-regulation and cardiac stress-induced reactivation of β-MHC in the Prox1 mutant heart (Fig.…”

Section: Resultsmentioning

confidence: 79%

Loss ofProx1in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

Petchey¹,

Risebro²,

Vieira

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance How cardiac and skeletal muscle function is maintained and regulated is important in terms of understanding normal muscle physiology and muscle-based disease (myopathy). The two striated muscle types are structurally and functionally divergent, suggesting alternate molecular regulation. However, our discovery that the transcription factor Prox1 controls the same fast skeletal muscle gene program in both cardiac and slow skeletal muscle is significant in assigning a common genetic mechanism to striated muscle development. These studies establish a novel model of human dilated cardiomyopathy and reveal how loss of a single factor underpins conversion of slow to fast skeletal muscle, with implications for the molecular specification of endurance (stamina) versus rapidly contractile muscle function (speed).

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“…Because small increases in ␤-MHC͞␣-MHC ratios correlate with impaired cardiac function (39,40) and because small elevations of ␤-MHC disproportionately slow contractile speed (40), it is conceivable that reduced ␤-MHC expression contributes to the increased myocardial contractility seen in our D2-overexpressing mice.…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 99%

“…For example, downregulation of K V 4.3-encoding I to and increased ␤-MHC͞␣-MHC ratio, both of which are prevented in D2-overexpressing mice subjected to pressure overload, have been suggested to contribute to depressed cardiac function in heart disease (39,40,43). On the other hand, although defective Ca 2ϩ handling in heart disease has also been linked to elevated NCX expression͞activity leading to SR Ca 2ϩ depletion and negative force-frequency relationships (35), no NCX expression changes were observed in mice after pressure overload, as reported previously (36,37).…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 99%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

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Myosin heavy chain gene expression in human heart failure.

Cited by 365 publications

References 42 publications

HDAC3-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

HDAC3-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

Loss ofProx1in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

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