2me‐SATP activates P2X4R and induces a secondary increase of Na+ pump and Na+/Ca++ currents in cardiac myocytes of P2X4R overexpression transgenic mice

Protooncogenes such as c-myc have been implicated in the transduction of growth signals in the cardiac myocyte. We examined whether increases in c-myc expression occur in murine heart in vivo as a generalized response to the pharmacological stimulation of myocyte growth. Both triiodothyronine (T3) and the beta-adrenergic agonist isoproterenol were demonstrated to induce a rapid and transient increase in cardiac c-myc mRNA abundance, which preceded an increase in cardiac mass. We then examined whether myocyte growth could be modulated by selectively altering cardiac c-myc expression. The model system used was a strain of transgenic mice exhibiting a 20-fold increase in cardiac c-myc expression. Although in nontransgenic mice the administration of T3 and isoproterenol resulted in similar increases in cardiac mass, in transgenic mice the degree of myocardial growth induced with T3 was significantly greater than that induced with isoproterenol (P less than 0.001). This study demonstrates that increasing the basal expression of c-myc in cardiac myocytes alters the growth response of the heart in vivo to certain hypertrophic stimuli and implicates the c-myc protooncogene in the transduction of selective hypertrophic growth signals in differentiated cardiac myocytes.

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Phospholamban-to-SERCA2 ratio controls the force-frequency relationship

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.3.h779 ◽

1999 ◽

Vol 276 (3) ◽

pp. H779-H785 ◽

Cited By ~ 17

Author(s):

Markus Meyer ◽

Wolfgang F. Bluhm ◽

Huaping He ◽

Steven R. Post ◽

Frank J. Giordano ◽

...

Keyword(s):

Sarcoplasmic Reticulum ◽

Transgenic Mice ◽

Cardiac Myocytes ◽

Cardiac Contractility ◽

Adult Rabbit ◽

Force Frequency ◽

Papillary Muscles ◽

Inhibitory Protein ◽

Frequency Relationship ◽

Myocyte Contractility

The force-frequency relationship (FFR) describes the frequency-dependent potentiation of cardiac contractility. The interaction of the sarcoplasmic reticulum Ca2+-adenosinetriphosphatase (SERCA2) with its inhibitory protein phospholamban (PLB) might be involved in the control of the FFR. The FFR was analyzed in two systems in which the PLB-to-SERCA2 ratio was modulated. Adult rabbit cardiac myocytes were transduced with adenovirus encoding for SERCA2, PLB, and β-galactosidase (control). After 3 days, the relative PLB/SERCA2 values were significantly different between groups (SERCA2, 0.5; control, 1.0; PLB, 4.5). SERCA2 overexpression shortened relaxation by 23% relative to control, whereas PLB prolonged relaxation by 39% and reduced contractility by 47% (0.1 Hz). When the stimulation frequency was increased to 1.5 Hz, myocyte contractility was increased by 30% in control myocytes. PLB-overexpressing myocytes showed an augmented positive FFR (+78%), whereas SERCA2-transduced myocytes displayed a negative FFR (−15%). A more negative FFR was also found in papillary muscles from SERCA2 transgenic mice. These findings demonstrate that the ratio of phospholamban to SERCA2 is an important component in the control of the FFR.

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Identification of Low and High Affinity Ouabain-Sensitive Na Pump Current in Voltage-Clamped Rat Cardiac Myocytes

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1992.tb43823.x ◽

1992 ◽

Vol 671 (1 Ion-Motive AT) ◽

pp. 440-442 ◽

Cited By ~ 5

Author(s):

JOSHUA R. BERLIN ◽

ALEXANDER J. FIELDING ◽

NOBUHIKO ISHIZUKA

Keyword(s):

Cardiac Myocytes ◽

Pump Current ◽

High Affinity ◽

Na Pump ◽

Rat Cardiac Myocytes

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Cardiac Gsα overexpression enhances L-type calcium channels through an adenylyl cyclase independent pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.16.9669 ◽

1998 ◽

Vol 95 (16) ◽

pp. 9669-9674 ◽

Cited By ~ 48

Author(s):

Alan S. Lader ◽

Yong-Fu Xiao ◽

Yoshihiro Ishikawa ◽

Yanning Cui ◽

Dorothy E. Vatner ◽

...

Keyword(s):

Protein Kinase ◽

Transgenic Mice ◽

Protein Kinase A ◽

Adenylyl Cyclase ◽

Cardiac Myocytes ◽

Receptor Activation ◽

Wild Type ◽

Α Subunit ◽

Kinase A

The α subunit of the stimulatory heterotrimeric G protein (Gsα) is critical for the β-adrenergic receptor activation of the cAMP messenger system. The role of Gsα in regulating cardiac Ca2+ channel activity, however, remains controversial. Cultured neonatal cardiac myocytes from transgenic mice overexpressing cardiac Gsα were used to assess the role of Gsα on the whole-cell Ca2+ currents (ICa). Cardiac myocytes from transgenic mice had a 490% higher peak ICa compared with those of either wild-type controls or Gsα-nonexpressing littermates. The effect of Gsα overexpression was mimicked by intracellular dialysis of wild-type cardiac myocytes with GTPγS-activated Gsα. This effect was not mediated by protein kinase A activation as intracellular perfusion with a protein kinase A inhibitor rendered the same degree of activation in either transgenic or wild-type myocytes also dialyzed with activated Gsα. The data indicate that Gsα overexpression is associated with a constitutive enhancement of ICa which is independent of the cAMP pathway and activation of endogenous adenylyl cyclase.

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Inducible regulation of human brain natriuretic peptide promoter in transgenic mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.1.h368 ◽

2001 ◽

Vol 280 (1) ◽

pp. H368-H376 ◽

Cited By ~ 28

Author(s):

Quan He ◽

Ding Wang ◽

Xiao-Ping Yang ◽

Oscar A. Carretero ◽

Margot C. LaPointe

Keyword(s):

Transgenic Mice ◽

Brain Natriuretic Peptide ◽

Cardiac Myocytes ◽

Natriuretic Peptide ◽

Luciferase Activity ◽

Left Ventricular ◽

Neonatal Rat ◽

Luciferase Reporter ◽

Coronary Artery Ligation

Studies have shown that brain natriuretic peptide (BNP) gene expression is rapidly induced in the infarcted heart and that plasma BNP levels reflect the degree of left ventricular dysfunction. Our previous in vitro work using transiently transfected neonatal rat cardiac myocytes has shown that the human BNP (hBNP) promoter, in particular a region extending from −127 to −40 relative to the start site of transcription, is more active in cardiac myocytes than in fibroblasts. To study tissue-specific and transcriptional regulation of the hBNP gene in vivo, we generated transgenic mice containing the proximal hBNP promoter (−408 to +100) coupled to a luciferase reporter gene. In four lines of transgenic mice, luciferase activity was ∼33- to 100-fold higher in the heart than in other tissues, including the whole brain. To test whether the transgene responded to a pathophysiological stimulus, we induced infarction by coronary artery ligation. Luciferase activity was fivefold higher in the infarcted region of the left ventricle at 48 h than in sham-operated animals and remained elevated for 4 wk. Endogenous BNP mRNA was similarly increased in the infarcted hearts of a separate group of mice. We conclude that 1) the proximal 408-bp region of the hBNP promoter confers cardiac-specific expression and 2) myocardial infarction activates the proximal hBNP promoter in vivo. These data suggest that we have a valid model for the study of basal and inducible regulation of the hBNP gene in vivo.

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