Biomedical subjects

Paramjit S Tappia

Publications and source records attributed to Paramjit S Tappia.

At least 19 recordsLinked to original sources

PubMed2006

Norepinephrine-induced changes in gene expression of phospholipase C in cardiomyocytes.

Previously, we have reported that norepinephrine (NE)-mediated cardiac hypertrophy may occur due to stimulation of alpha1-adrenoceptors and phospholipase C (PLC) activity. Since the signal transduction mechanisms involving PLC isozymes in cardiomyocytes are not well established, the present study was conducted to test the hypothesis that stimulation of cardiac PLC activity by NE increases the gene expression for PLC isozymes via a PKC and ERK 1/2-dependent pathway. For this purpose, mRNA levels for PLC beta1, beta3, gamma1, and delta1 isozymes were determined in isolated adult rat cardiomyocytes upon incubation in the absence and presence of NE. The NE-induced increases in PLC isozyme mRNA levels were not only attenuated by prazosin, an inhibitor of alpha1-adrenergic receptor, but also by U73122, an inhibitor of PLC activity. Alterations in NE-induced PLC gene expression by both prazosin and U73122 were associated with inhibition of PLC activity. The inhibition of NE-stimulated PLC gene expression by bisindolylmaleimide, a PKC inhibitor, and PD98059, an ERK1/2 inhibitor, indicated that PKC-MAPK signaling may be involved in this signal transduction pathway. The observed NE-induced changes in gene expression in the presence of different inhibitors were associated with corresponding changes in the protein content. Furthermore, significant increases in mRNA levels and protein contents for all PLC isozymes were found in cardiomyocytes treated with phorbol 12-myristate 13-acetate, a PKC activator. These data indicate that PLC isozymes may regulate their own gene expression through a PKC and ERK 1/2-dependent pathway in a cycle of events associated with the cardiomyocyte hypertrophic response.

Animals↗

PubMed2006

Oxidative stress and redox regulation of phospholipase D in myocardial disease.

Oxidative stress may be viewed as an imbalance between reactive oxygen species (ROS) and oxidant production and the state of glutathione redox buffer and antioxidant defense system. Recently, a new paradigm of redox signaling has emerged whereby ROS and oxidants can function as intracellular signaling molecules, where ROS- and oxidant-induced death signal is converted into a survival signal. It is now known that oxidative stress is involved in cardiac hypertrophy and in the pathogenesis of cardiomyopathies, ischemic heart disease and congestive heart failure. Phospholipase D (PLD) is an important signaling enzyme in mammalian cells, including cardiomyocytes. PLD catalyzes the hydrolysis of phosphatidylcholine to produce phosphatidic acid (PA). Two mammalian PLD isozymes, PLD1 and PLD2 have been identified, characterized and cloned. The importance of PA in heart function is evident from its ability to stimulate cardiac sarcolemmal membrane and sarcoplasmic reticular Ca2+-related transport systems and to increase the intracellular concentration of free Ca2+ in adult cardiomyocytes and augment cardiac contractile activity of the normal heart. In addition, PA is also considered an important signal transducer in cardiac hypertrophy. Accordingly, this review discusses a role for redox signaling mediated via PLD in ischemic preconditioning and examines how oxidative stress affects PLD in normal hearts and during different myocardial diseases. In addition, the review provides a comparative account on the regulation of PLD activities in vascular smooth muscle cells under conditions of oxidative stress.

Animals↗

PubMed2006

Inhibition of phospholipase C-gamma 1 augments the decrease in cardiomyocyte viability by H2O2.

The present study was conducted to examine the role of a major cardiac phospholipase C (PLC) isozyme, PLC-gamma 1, in cardiomyocytes during oxidative stress. Left ventricular cardiomyocytes were isolated by collagenase digestion from adult male Sprague-Dawley rats (250-300 g) and treated with 20, 50, and 100 microM H2O2 for 15 min. A concentration-dependent (up to 50 microM) increase in the mRNA level and membrane protein content of PLC-gamma 1 was observed with H2O2 treatment. Furthermore, PLC-gamma 1 was activated in response to H2O2, as revealed by an increase in the phosphorylation of its tyrosine residues. There was a marked increase in the phosphorylation of the antiapoptotic protein Bcl-2 by H2O2; this change was attenuated by a PLC inhibitor, U-73122. Although both protein kinase C (PKC)-delta and -epsilon protein contents were increased in the cardiomyocyte membrane fraction in response to H2O2, PKC-epsilon activation, unlike PKC-delta, was attenuated by U-73122 (2 microM). Inhibition of PKC-epsilon with inhibitory peptide (0.1 microM) prevented Bcl-2 phosphorylation. Moreover, different concentrations (0.05, 0.1, and 0.2 microM) of this peptide augmented the decrease in cardiomyocyte viability in response to H2O2. In addition, a decrease in cardiomyocyte viability, as assessed by trypan blue exclusion, due to H2O2 was also seen when cells were pretreated with U-73122 and was as a result of increased apoptosis. It is therefore suggested that PLC-gamma 1 may play a role in cardiomyocyte survival during oxidative stress via PKC-epsilon and phosphorylation of Bcl-2.

Animals↗

PubMed2006

Gender differences in the cardiac response to dietary conjugated linoleic acid isomers.

The present study was undertaken to assess the heart function, by the in vivo catheterization technique, of healthy male and female Sprague-Dawley rats fed different conjugated linoleic acid (CLA) isomers, (cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12)) individually and in combination (50:50 mix as triglyceride or fatty acids) from 4 to 20 weeks of age. Whereas the triglyceride form of the CLA isomer mix lowered the heart rate, the rate of contraction (+dP/dt) and rate of relaxation (-dP/dt), systolic and diastolic pressures, mean arterial pressure, and the left ventricular systolic pressure were higher in male rats as compared with all the other dietary groups. In contrast, there were no significant effects in the cardiac function of the female rats in response to the CLA isomer mix in triglyceride form. Whereas the heart rate, +dP/dt, and left ventricular systolic pressure were lower in male rats fed the t10,c12 CLA isomer alone, the heart rate of the female rats was higher, but the systolic pressure, +dP/dt, and mean arterial pressure were lower compared with the control group. Also, the left ventricular end-diastolic pressure was specifically higher in the female rats in response to free fatty acids-containing CLA mix. Furthermore, an additive effect of the free fatty acids-containing CLA mix was seen in the +dP/dt and -dP/dt of female rats compared with the control group. These results indicate that CLA isomers exert differential effects on heart function and suggest the need for a complete evaluation of the benefits, interactions, and potential side effects of each isomer.

Animals↗

PubMed2006

Subcellular remodeling as a viable target for the treatment of congestive heart failure.

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.

Animals↗

PubMed2006

Blockade of the renin-angiotensin system attenuates sarcolemma and sarcoplasmic reticulum remodeling in chronic diabetes.

Although the defects in the sarcolemma (SL) and sarcoplasmic reticulum (SR) membranes are known to be associated with cardiac dysfunction in chronic diabetes, very little information regarding the mechanisms of these membrane abnormalities is available in the literature. For this reason, rats were treated daily for 8 weeks with and without enalapril, an angiotensin-converting enzyme inhibitor, or losartan, an angiotensin receptor antagonist, 3 days after inducing diabetes with an injection of streptozocin. Treatment of diabetic animals with both enalapril and losartan attenuated alterations in cardiac function and the left ventricular redox potential without any changes in the increased plasma glucose or reduced plasma insulin levels. The SL Na+-K+ ATPase, Ca2+ pump, Na+-dependent Ca2+-uptake, Ca2+-channel density, and low-affinity Ca2+-binding activities were depressed whereas Ca2+ ecto-ATPase activity was increased in the diabetic heart. Furthermore, the SR Ca2+-release and Ca2+-pump activities in the diabetic hearts were decreased without any changes in the Mg2+-ATPase activity. These alterations in SL and SR membranes in diabetic animals were partly prevented by treatments with enalapril and losartan. The results suggest that the activation of the renin-angiotensin system plays an important role in diabetes-induced changes in SL and SR membranes as well as cardiac function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2006

Role of nutrition in the development of the fetal cardiovascular system.

Emerging evidence demonstrates that heart disease may originate during fetal development. This review will focus on the role of maternal nutrition in the development of the fetal cardiovascular system. Emphasis will be placed upon the concept that nutritional inadequacies during gestation may be major programming stimuli that alter fetal cardiac, as well as vascular, physiology and predispose an individual to cardiovascular abnormalities in postnatal life. It is hypothesized that this research area will yield new information, resulting in improved fetal nutrition, growth and development through efficient maternal nutrition before and during pregnancy and will form the basis for nutritional strategies for the primary prevention of cardiovascular disease.

Cardiovascular Diseases↗

PubMed2005

Phospholipid profile of developing heart of rats exposed to low-protein diet in pregnancy.

Although the myocardial phospholipid and fatty acid content have profound effects on the heart function, very little information is available on the effects of restricted maternal protein intake during pregnancy on the phospholipid profile and fatty acid content of the developing heart. The present study was therefore undertaken to examine the effect of pregnant dams fed diets containing either 180 (normal) or 90 (low) g/kg casein diet for 2 wk before mating and throughout pregnancy on myocardial phospholipid and fatty acid content of male offspring. Whereas no changes in phosphatidylcholine and phosphatidylethanolamine were detected, increases in lysophosphatidylcholine, phosphatidylserine, and sphingomyelin were seen in the hearts of offspring in the low-protein (LP) group. Analysis of cardiac fatty acids revealed that although the saturated fatty acid (myristate, palmitate, and stearate) levels were significantly reduced, the unsaturated fatty acid (linoleate, arachidonate, and decosahexanoate) levels were significantly increased in the developing heart in the LP group. Furthermore, assessment of nuclear transcription factors involved in regulation of cardiac metabolism revealed a decrease in myocyte enhancer factor-2C mRNA levels in the LP group, whereas an increase in the mRNA amount of peroxisome proliferator-activated receptor-alpha was observed in this group. These results demonstrate that maternal LP diet can induce changes in the phospholipid profile and fatty acid content of the developing heart, which may have implications for metabolism of the neonatal heart.

Animals↗

PubMed2005

Differential changes in phospholipase D and phosphatidate phosphohydrolase activities in ischemia-reperfusion of rat heart.

Phospholipase D (PLD2) produces phosphatidic acid (PA), which is converted to 1,2 diacylglycerol (DAG) by phosphatidate phosphohydrolase (PAP2). Since PA and DAG regulate Ca(2+) movements, we examined PLD2 and PAP2 in the sarcolemma (SL) and sarcoplasmic reticular (SR) membranes from hearts subjected to ischemia and reperfusion (I-R). Although SL and SR PLD2 activities were unaltered after 30 min ischemia, 5 min reperfusion resulted in a 36% increase in SL PLD2 activity, whereas 30 min reperfusion resulted in a 30% decrease in SL PLD2 activity, as compared to the control value. SR PLD2 activity was decreased (39%) after 5 min reperfusion, but returned to control levels after 30 min reperfusion. Ischemia for 60 min resulted in depressed SL and SR PLD2 activities, characterized with reduced V(max) and increased K(m) values, which were not reversed during reperfusion. Although the SL PAP2 activity was decreased (31%) during ischemia and at 30 min reperfusion (28%), the SR PAP2 activity was unchanged after 30 min ischemia, but was decreased after 5 min reperfusion (25%) and almost completely recovered after 30 min reperfusion. A 60 min period of ischemia followed by reperfusion caused an irreversible depression of SL and SR PAP2 activities. Our results indicate that I-R induced cardiac dysfunction is associated with subcellular changes in PLD2 and PAP2 activities.

Animals↗

PubMed2005

Modification of sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchanger expression in heart failure by blockade of renin-angiotensin system.

The activities of both sarcolemmal (SL) Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchanger, which maintain the intracellular cation homeostasis, have been shown to be depressed in heart failure due to myocardial infarction (MI). Because the renin-angiotensin system (RAS) is activated in heart failure, this study tested the hypothesis that attenuation of cardiac SL changes in congestive heart failure (CHF) by angiotensin-converting enzyme (ACE) inhibitors is associated with prevention of alterations in gene expression for SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchanger. CHF in rats due to MI was induced by occluding the coronary artery, and 3 wk later the animals were treated with an ACE inhibitor, imidapril (1 mg.kg(-1).day(-1)), for 4 wk. Heart dysfunction and cardiac hypertrophy in the infarcted animals were associated with depressed SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchange activities. Protein content and mRNA levels for Na(+)/Ca(2+) exchanger as well as Na(+)-K(+)-ATPase alpha(1)-, alpha(2)- and beta(1)-isoforms were depressed, whereas those for alpha(3)-isoform were increased in the failing heart. These changes in SL activities, protein content, and gene expression were attenuated by treating the infarcted animals with imidapril. The beneficial effects of imidapril treatment on heart function and cardiac hypertrophy as well as SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchange activities in the infarcted animals were simulated by enalapril, an ACE inhibitor, and losartan, an angiotensin receptor antagonist. These results suggest that blockade of RAS in CHF improves SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchange activities in the failing heart by preventing changes in gene expression for SL proteins.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Imidapril treatment improves the attenuated inotropic and intracellular calcium responses to ATP in heart failure due to myocardial infarction.

1. Adenosine 5'-triphosphate (ATP) is known to augment cardiac contractile activity and cause an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in isolated cardiomyocytes. However, no information regarding the ATP-mediated signal transduction in the myocardium in congestive heart failure (CHF) is available. 2. CHF due to myocardial infarction (MI) in rats was induced by the occlusion of the left coronary artery for 8 weeks. The positive inotropy due to ATP was depressed in failing hearts. Treatment of 3 weeks infarcted animals with imidapril (1 mg kg(-1) day(-1)) for a period of 5 weeks improved the left ventricle function and decreased the attenuation of inotropic response to ATP. 3. ATP-induced increase in [Ca(2+)](i) was significantly depressed in cardiomyocytes isolated from the failing heart and this change was partially attenuated by imidapril treatment. However, the binding characteristics of (35)S-labeled adenosine 5'-(gamma-thio) triphosphate in sarcolemma isolated from the failing heart remained unaltered. 4. ATP-induced increase in [Ca(2+)](i) was depressed by verapamil and cibacron blue in both control and failing heart cardiomyocytes; however, the ATP response in the failing hearts, unlike the control preparations, was not decreased by ryanodine. This insensitivity to ryanodine was attenuated by imidapril treatment. 5. Treatment of infarcted rats with enalapril and losartan produced effects similar to imidapril. 6. These findings indicate that the positive inotropic response to ATP and ATP-induced increase in [Ca(2+)](i) in cardiomyocytes are impaired in heart failure. Furthermore, blockade of renin angiotensin system prevented the impairment of the ATP-mediated inotropic and [Ca(2+)](i) responses in the failing heart.

Adenosine Triphosphate↗

PubMed2005

Prenatal exposure to maternal undernutrition induces adult cardiac dysfunction.

An adverse environmental experience of the growing fetus may lead to permanent changes in the structure and function of organs that may predispose the individual to chronic diseases in later life; however, nothing is known about the occurrence and mechanisms of heart failure. We employed a rat model in which pregnant dams were fed diets containing either 180 g (normal) or 90 g (low) casein/kg for 2 weeks before mating and throughout pregnancy. The ejection fraction (EF) of the pups exposed to the low-protein (LP) diet was severely depressed in the first 2 weeks of life and was associated with an increase in cardiomyocyte apoptosis. This early depressed cardiac function was followed by progressive recovery and normalization of the EF of the offspring in the LP group. The left ventricular (LV) internal diameters were increased between 24 h and 84 d (12 weeks) of age in the LP-exposed group. Although between 3 d and 2 weeks of age the LV wall of the heart in the LP group was thinner, a progressive increase in LV wall thickness was seen. At 40 weeks of age, although the EF was normal, a two-fold elevation in LV end-diastolic pressure, reduced cardiac output, decreased maximum rates of contraction and relaxation, and reduced mean arterial pressure were observed. Our findings demonstrate that exposure of the developing fetus to a maternal LP diet programs cardiac dysfunction in the offspring in later life.

Animals↗

PubMed2004

Inhibition of PLC improves postischemic recovery in isolated rat heart.

The Ca2+-dependent PLC converts phosphatidylinositol 4,5-bisphosphate to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Because these products modulate Ca2+ movements in the myocardium, PLC may also contribute to a self-perpetuating cycle that exacerbates cardiomyocyte Ca2+-overload and subsequent cardiac dysfunction in ischemia-reperfusion (I/R). Although we have reported that I/R-induced changes in PLC isozymes might contribute to cardiac dysfunction, the present study was undertaken to examine the beneficial effects of the PLC inhibitor, U-73122, as well as determining the role of Ca2+ on the I/R-induced changes in PLC isozymes. Isolated rat hearts were subjected to global ischemia 30 min, followed by 5 or 30 min of reperfusion. Pretreatment of hearts with U-73122 (0.5 microM) significantly inhibited DAG and Ins(1,4,5)P3 production in I/R and was associated with enhanced recovery of cardiac function as indicated by measurement of left ventricular (LV) end-diastolic pressure (EDP), LV diastolic pressure (LVDP), maximum rate of pressure development (+dP/dtmax), and maximum rate of LV pressure decay (-dP/dtmax). Verapamil (0.1 microM) partially prevented the increase in sarcolemmal (SL) PLC-beta1 activity in ischemia and the decrease in its activity during the reperfusion phase as well as elicited a partial protection of the depression in SL PLC-delta1 and PLC-gamma1 activities during the ischemic phase and attenuated the increase during the reperfusion period. Although these changes were associated with an improved myocardial recovery after I/R, verapamil was less effective than U-73122. Perfusion with high Ca2+ resulted in the activation of the PLC isozymes studied and was associated with a markedly increased LVEDP and reduced LVDP, +dP/dtmax, and -dP/dtmax. These results suggest that inhibition of PLC improves myocardial recovery after I/R.

Animals↗

PubMed2004

Phospholipase C may be involved in norepinephrine-induced cardiac hypertrophy.

Cardiac hypertrophy is characterized by increased cardiomyocyte size, mRNA levels for atrial natriuretic factor (ANF), and protein synthesis. Although activation of the phosphoinositide-specific phospholipase C (PLC) leads to the generation of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate, the involvement of PLC in hypertrophic response remains to be fully understood. The present study was therefore undertaken to examine if the inhibition of PLC activity is associated with a decrease in ANF expression and protein synthesis in cardiomyocytes, due to norepinephrine (NE), a known hypertrophic agent. NE resulted in an increase in ANF gene expression and protein synthesis in adult rat cardiomyocytes, these effects of NE were attenuated by a PLC inhibitor, U73122. The NE-induced increase in ANF gene expression and protein synthesis was also inhibited by an alpha-adrenoceptor blocker, prazosin. Both U73122 and prazosin depressed the NE-induced increase in DAG production in cardiomyocytes. These results indicate that the alpha-adrenoceptor mediated PLC activation may be involved in the process of NE-induced cardiac hypertrophy.

Animals↗

PubMed2004

Phospholipase C gene expression, protein content, and activities in cardiac hypertrophy and heart failure due to volume overload.

Volume overload due to arteriovenous (AV) shunt results in cardiac hypertrophy followed by the progression to heart failure. The phosphoinositide phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP(2)) to 1,2-diacylglycerol (DAG) and inositol (1,4,5)-trisphosphate (IP(3)), which are known to influence cardiac function. Therefore, we examined the time course of changes in DAG and IP(3) as well as PLC isozyme gene expression, protein content, and activities in cardiac hypertrophy and heart failure induced by AV shunt in Sprague-Dawley rats by the needle technique. An increase in the left ventricle (LV)-to-body weight ratio demonstrated that LV hypertrophy was established at 4 wk after the induction of the shunt. PLC-beta(1) activity was increased two- and sevenfold at 3 days and 1 and 2 wk after the induction of volume overload, respectively. These changes were associated with increases in the mRNA and sarcolemmal (SL) protein content; however, no changes in PLC-beta(1) were detected at 4 wk. On the other hand, a significant increase in PLC-gamma(1) activity as well as mRNA and SL protein was seen at 3 days and 4 wk. A progressive decrease in PLC-delta(1) activity with concomitant reductions in the gene expression and SL protein abundance was detected during 1 to 4 wk. Activity of gamma(1)- and delta(1)-isozymes was significantly depressed during the 8- and 16-wk time points, whereas beta(1)-isozyme was increased significantly during these time points. A progressive decrease in the SL PIP(2) content was observed during cardiac hypertrophy and heart failure. Our findings indicate that PLC isozyme signaling processes are increased in hypertrophy and decreased in heart failure due to volume overload.

Animals↗

PubMed2004

Defective phosphatidic acid-phospholipase C signaling in diabetic cardiomyopathy.

The effects of exogenous phosphatidic acid (PA) on Ca2+ transients and contractile activity were studied in cardiomyocytes isolated from chronic streptozotocin-induced diabetic rats. In control cells, 25 microM PA induced a significant increase in active cell shortening and Ca2+ transients. PA increased IP3 generation in the control cardiomyocytes and its inotropic effects were blocked by a phospholipase C inhibitor. In cardiomyocytes from diabetic rats, PA induced a 25% decrease in active cell shortening and no significant effect on Ca2+ transients. Basal and PA-induced IP3 generation in diabetic rat cardiomyocytes was 3-fold lower as compared to control cells. Sarcolemmal membrane PLC activity was impaired. Insulin treatment of the diabetic animals resulted in a partial recovery of PA responses. Our results, therefore, identify an important defect in the PA-PLC signaling pathway in diabetic rat cardiomyocytes, which may have significant implications for heart dysfunction during diabetes.

Animals↗

PubMed2004

Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy.

Phospholipase C (PLC) activity is known to influence cardiac function. This study was undertaken to examine the status of PLC beta3 in the cardiac cell plasma membrane (sarcolemma, SL) in an experimental model of chronic diabetes. SL membrane was isolated from diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mg/kg body weight). The total SL PLC was decreased in diabetes and was associated with a decrease in SL PLC beta3 activity, which immunofluorescence in frozen diabetic left ventricular tissue sections revealed to be due to a decrease in PLC beta3 protein abundance. In contrast, the SL abundance of Gqalpha was significantly increased during diabetes. These changes were associated with a loss of contractile function (+/- dP/dt). A 2-week insulin treatment of 6-week diabetic animals partially normalized all of these parameters. These findings suggest a defect in PLC beta3-mediated signaling processes may contribute to the cardiac dysfunction seen during diabetes.

Animals↗

PubMed2004

Influence of long-term treatment of imidapril on mortality, cardiac function, and gene expression in congestive heart failure due to myocardial infarction.

Although it is generally accepted that the efficacy of imidapril, an angiotensin-converting enzyme inhibitor, in congestive heart failure (CHF) is due to improvement of hemodynamic parameters, the significance of its effect on gene expression for sarcolemma (SL) and sarcoplasmic reticulum (SR) proteins has not been fully understood. In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ ATPase and Na+ -Ca2+ exchanger as well as SR Ca2+ pump ATPase, Ca2+ release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction. Heart failure subsequent to myocardial infarction was induced by occluding the left coronary artery in rats, and treatment with imidapril (1 mg.kg(-1).day(-1)) was started orally at the end of 3 weeks after surgery and continued for 37 weeks. The animals were assessed hemodynamically and the heart and lung were examined morphologically. Some hearts were immediately frozen at -70 degrees C for the isolation of RNA as well as SL and SR membranes. The mortality of imidapril-treated animals due to heart failure was 31% whereas that of the untreated heart failure group was 64%. Imidapril treatment improved cardiac performance, attenuated cardiac remodeling, and reduced morphological changes in the heart and lung. The depressed SL Na+/K+ ATPase and increased SL Na+-Ca2+ exchange activities as well as reduced SR Ca2+ pump and SR Ca2+ release activities in the failing hearts were partially prevented by imidapril. Although changes in gene expression for SL Na+/K+ ATPase isoforms as well as Na+-Ca2+ exchanger and SR phospholamban were attenuated by treatments with imidapril, no alterations in mRNA levels for SR Ca2+ pump proteins and Ca2+ release channels were seen in the untreated or treated rats with heart failure. These results suggest that the beneficial effects of imidapril in CHF may be due to improvements in cardiac performance and changes in SL gene expression.

Angiotensin-Converting Enzyme Inhibitors↗