Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy

Minamisawa, Susumu; Sato, Yoji; Tatsuguchi, Yuriko; Fujino, Tomofumi; Imamura, Shinichiro; Uetsuka, Yoshio; Nakazawa, Makoto; Matsuoka, Rumiko

doi:10.1016/s0006-291x(03)00526-6

Cited by 78 publications

(55 citation statements)

References 16 publications

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“…Reduction of PLB through antisense suppression or genetic ablation increased sarcoplasmic reticulum calcium cycling and improved cardiac myocyte survival and cardiac function (22,23). In contrast, overexpression of PLB through an increase in PLB promoter activity was associated with hypertrophic cardiomyopathy (24), and cardiac-directed expression of PLB resulted in depressed contractility and cardiomyopathy after ␤-adrenergic receptor stimulation (25). Reduced PLB expression resulting from AC VI expression would be expected to have a favorable impact on cardiac function and may be an important mechanism by which AC, in contrast to other elements that increase intracellular cAMP, has a favorable effect in the failing heart.…”

Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Gao

Tang

Guo

et al. 2004

Journal of Biological Chemistry

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Cardiac-directed expression of adenylyl cyclase type VI (AC VI ) increases stimulated cAMP production, improves heart function, and increases survival in cardiomyopathy. In contrast, pharmacological agents that increase intracellular levels of cAMP have detrimental effects on cardiac function and survival. We wondered whether effects that are independent of cAMP might be responsible for these salutary outcomes associated with AC VI expression. We therefore conducted a series of experiments focused on how gene transcription is influenced by AC VI in cultured neonatal rat cardiac myocytes, with a particular focus on genes that might influence cardiac function. We found that overexpression of AC VI down-regulated mRNA and protein expression of phospholamban, an inhibitor of the sarcoplasmic reticulum Ca 2؉ -ATPase. We determined that the cAMPresponsive-like element in the phospholamban (PLB) promoter was critical for down-regulation by AC VI . Overexpression of AC VI did not alter the expression of CREB, CREM, ATF1, ATF2, or ATF4 proteins. In contrast, overexpression of AC VI increased expression of ATF3 protein, a suppressor of transcription. Following AC VI gene transfer, when cardiac myocytes were stimulated with isoproterenol or NKH477, a water-soluble forskolin analog that directly stimulates AC, expression of ATF3 protein was increased even more, which correlated with reduced expression of PLB. We then showed that AC VI -induced ATF3 protein binds to the cAMP-responsive-like element on the PLB promoter and that overexpression of ATF3 in cardiac myocytes inhibits PLB promoter activity. These findings indicate that AC VI has effects on gene transcription that are not directly dependent on cAMP generation. Adenylyl cyclase (AC)1 is the effector molecule in the ␤-adrenergic receptor-G-protein-AC signaling pathway in cardiac myocytes and other cells. Previous studies showed that the amount of AC sets a limit on the ability of cardiac myocytes to generate cAMP (1), and cardiac-directed expression of AC type VI (AC VI ) has pronounced favorable effects on cardiovascular function in normal and failing hearts (2-6).The mechanisms explaining these favorable effects of AC VI are not precisely known. The most direct explanation is that the benefits stem from increased intracellular levels of cAMP; this explanation is contrary to current dogma in heart failure which asserts that inotropic agents that increase cAMP are bad for the heart. Indeed, pharmacological agents that stimulate the ␤-adrenergic receptor or decrease the breakdown of cAMP increase cardiac function but do not appear to prolong life (7-9). In contrast, AC VI , a dominant AC isoform in mammalian cardiac myocytes, improves global cardiac function, attenuates myocardial hypertrophy, and increases survival in murine cardiomyopathy (3, 4). However, when cardiac-directed ␤-adrenergic receptor expression is used to treat this same model, life is shortened (10), underscoring the marked differences evoked by these signaling elements, both of which are associated w...

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Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Gao

Tang

Guo

et al. 2004

Journal of Biological Chemistry

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“…Moreover, promoter mutations of PLN, which increased transcription, were recently reported in HCM. 103,104 As transgenic mice over-expressing PLN did not show cardiac hypertrophy, rather they showed systolic dysfunction, 105 pathological significance of PLN promoter mutations in HCM remains to be clarified.…”

Section: Other Mutations In Dcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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“…In particular, cellular proteins involved in calcium-induced calcium release, which allows for coordinated myocyte contraction, have been targeted as candidates in the pathogenesis of cardiomyopathy [20][21][22]. Mutations in promoter and coding region of phospholamban, a regulator of the sarcoplasmic reticulum calcium ATPase (SERCA2a) and a regulator of calcium homeostasis within the cell, have been identified in hypertrophic and dilated cardiomyopathy respectively [23,24]. These findings suggest that mutations in proteins involved in intracellular calcium homeostasis might be linked to HCM and may provide insight into novel mechanisms of HCM pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Landstrom

Weisleder

Batalden

et al. 2007

Journal of Molecular and Cellular Cardiology

163

157

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Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy

Cited by 78 publications

References 16 publications

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

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