671 Transgenic rat hearts overexpressing SERCA2a show improved contractility under baseline conditions and pressure overload

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 inhibitor [CG-42112A (10(-8) M]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.

Download Full-text

Expression and cellular distribution of heat-shock and nuclear oncogene proteins in rat hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.261.5.h1443 ◽

1991 ◽

Vol 261 (5) ◽

pp. H1443-H1451 ◽

Cited By ~ 2

Author(s):

L. H. Snoeckx ◽

F. Contard ◽

J. L. Samuel ◽

F. Marotte ◽

L. Rappaport

Keyword(s):

Heat Shock ◽

Cardiac Development ◽

Pressure Overload ◽

Adult Rats ◽

Coronary Smooth Muscle ◽

Rat Hearts ◽

Nonmuscle Cells ◽

Ontogenic Development ◽

Coronary Endothelium ◽

Myocardial Muscle

An early, transient accumulation of mRNAs of the protooncogenes c-fos and c-myc and the heat-shock protein HSP70 has been described in hypertrophying rat hearts. It is unclear 1) in which cardiac cell type-these gene activations occur and 2) whether the corresponding proteins are translated. We studied protein expression in rat hearts during ontogenic development and under stress conditions associated with pressure overload with the use of immunofluorescent techniques. During cardiac development no HSP70 could be detected. c-Fos was expressed consistently after birth but only in coronary smooth muscle cells, and c-Myc was found exclusively in adult coronary endothelium and myocardial nonmuscle cells. In adult rats, HSP70 and, to a lesser extent, c-Fos were induced in myocardial muscle and some nonmuscle cells within 3 h following methohexital sodium anesthesia. A similar, more intense immunolabeling of these peptides was observed after thoracotomy and/or aortic stenosis. The coronary c-Fos and c-Myc labeling remained unchanged in these conditions. Thus the expression in cardiac muscle and nonmuscle cells of the three peptides differs and depends on different triggers.

Download Full-text

Recruitment of NADH shuttling in pressure-overloaded and hypertrophic rat hearts

AJP Cell Physiology ◽

10.1152/ajpcell.00576.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. C1880-C1886 ◽

Cited By ~ 21

Author(s):

E. Douglas Lewandowski ◽

J. Michael O'Donnell ◽

Thomas D. Scholz ◽

Natalia Sorokina ◽

Peter M. Buttrick

Keyword(s):

Redox State ◽

Pressure Overload ◽

Compensatory Hypertrophy ◽

Dynamic Mode ◽

Aortic Banding ◽

Isolated Hearts ◽

Rat Hearts ◽

Energy Synthesis ◽

Mitochondrial Oxidation ◽

C Nmr

Glucose metabolism in the heart requires oxidation of cytosolic NADH from glycolysis. This study examines shuttling reducing equivalents from the cytosol to the mitochondria via the activity and expression of the oxoglutarate-malate carrier (OMC) in rat hearts subjected to 2 wk (Hyp2, n = 6) and 10 wk (Hyp10, n = 8) of pressure overload hypertrophy vs. that of sham-operated rats (Sham2, n = 6; and Sham10, n = 7). Moderate aortic banding produced increased atrial natriuretic factor (ANF) mRNA expression at 2 and 10 wk, but only at 10 wk did hearts develop compensatory hypertrophy (33% increase, P < 0.05). Isolated hearts were perfused with the short-chain fatty acid [2,4-13C2]butyrate (2 mM) and glucose (5 mM) to enable dynamic-mode 13C NMR of intermediate exchange across OMC. OMC flux increased before the development of hypertrophy: Hyp2 = 9.6 ± 2.1 vs. Sham2 = 3.7 ± 1.2 μM·min−1·g dry wt−1, providing an increased contribution of cytosolic NADH to energy synthesis in the mitochondria. With compensatory hypertrophy, OMC flux returned to normal: Hyp10 = 3.9 ± 1.7 vs. Sham10 = 3.8 ± 1.2 μM·g−1·min−1. Despite changes in activity, no differences in OMC expression occurred between Hyp and Sham groups. Elevated OMC flux represented augmented cytosolic NADH shuttling, coupled to increased nonoxidative glycolysis, in response to hypertrophic stimulus. However, development of compensatory hypertrophy moderated the pressure-induced elevation in OMC flux, which returned to control levels. The findings indicate that the challenge of pressure overload increases cytosolic redox state and its contribution to mitochondrial oxidation but that hypertrophy, before decompensation, alleviates this stress response.

Download Full-text

Activation of regenerating gene Reg in rat and human hearts in response to acute stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01206.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. H277-H284 ◽

Cited By ~ 19

Author(s):

Tatsuya Kiji ◽

Yoshiko Dohi ◽

Shin Takasawa ◽

Hiroshi Okamoto ◽

Akitaka Nonomura ◽

...

Keyword(s):

Myocardial Infarction ◽

Transcriptional Activation ◽

Acute Stress ◽

Pressure Overload ◽

Coronary Artery Ligation ◽

Aortic Constriction ◽

Artery Ligation ◽

Receptor System ◽

Rat Hearts ◽

Coronary Ligation

Recently, the regenerating gene ( Reg) has been documented to play an important role in various regenerating tissues, but it is unknown whether the Reg gene could be activated in the heart. The aim of this study was to reveal the transcriptional activation of Reg in the heart in response to heart stress. We first found REG-1 protein expression in human hearts obtained from autopsied patients who died of myocardial infarction. REG protein was immunohistochemically stained in a fine granular pattern in the cytoplasm of cardiomyocytes. To demonstrate the activation profiles of Reg gene expression in the heart, we quantified the levels of Reg-1 mRNA in rat hearts after coronary artery ligation using real-time RT-PCR. Transient Reg-1 mRNA activation, peaking at 12 h after coronary ligation, was observed mainly in the atria, which was sevenfold higher compared with hearts with pressure overload due to aortic constriction. In contrast, Reg receptor mRNA was expressed intensely in damaged ventricles. Furthermore, Western blot analysis showed the corresponding pattern of Reg protein secretion into the serum after loading, and circulating levels of the protein after myocardial infarction were higher than those after aortic constriction. In conclusion, our results demonstrate for the first time the presence of the Reg/Reg receptor system in damaged hearts. In view of emerging evidence of Reg for tissue regeneration in a variety of tissues/organs, it is proposed that the damaged heart may be a target for Reg action and that Reg may protect against acute heart stress.

Download Full-text

Decreased rates of substrate oxidation in vitro predict the onset of heart failure in rat hearts with pressure overload in vivo

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0029-1191597 ◽

2009 ◽

Vol 56 (S 01) ◽

Author(s):

G Faerber ◽

G Pytel ◽

M Schwarzer ◽

A Schrepper ◽

P Amorim ◽

...

Keyword(s):

Heart Failure ◽

Pressure Overload ◽

Substrate Oxidation ◽

Rat Hearts

Download Full-text

Hypertrophy alters effect of Ins(1,4,5)P3 on Ca2+ release in skinned rat heart muscle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.260.5.h1612 ◽

1991 ◽

Vol 260 (5) ◽

pp. H1612-H1618 ◽

Cited By ~ 2

Author(s):

N. Furukawa ◽

A. L. Bassett ◽

T. Furukawa ◽

R. J. Myerburg ◽

S. Kimura

Keyword(s):

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Contractile Dysfunction ◽

Body Weight Ratio ◽

Rat Hearts ◽

Inositol 1,4,5 Trisphosphate ◽

Normal Rat ◽

Skinned Cardiac Fibers

The effects of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] on the ability of the sarcoplasmic reticulum (SR) to accumulate and release Ca2+ and on the Ca2+ sensitivity of the contractile proteins were investigated using chemically (saponin) skinned cardiac fibers (60–120 microns diam) obtained from normal and pressure-overloaded hypertrophied rat left ventricles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta 3-6 wk before study. Age- and weight-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio by 45%. Ins(1,4,5)P3 at a concentration of 10 microM did not change the Ca(2+)-tension relationship at Ca2+ concentrations of 10(-7) to 10(-5) M in either normal or hypertrophied fibers. Ins(1,4,5)P3 also did not influence Ca2+ uptake by the SR in either normal or hypertrophied fibers. Ins(1,4,5)P3 did not induce Ca2+ release from the SR directly in either group. However, pretreatment with Ins(1,4,5)P3 enhanced the 5 mM caffeine-induced Ca2+ release by 80.5 +/- 22.7% in normal fibers enhances, rather than directly induces, SR Ca2+ release in normal rat hearts and that sustained pressure overload diminishes the response of the SR Ca(2+)-release system to Ins(1,4,5)P3, an action that may be partly responsible for contractile dysfunction in cardiac hypertrophy.

Download Full-text