Nobuakira Takeda

Changes in sarcolemmal PLC isoenzymes in postinfarct congestive heart failure: partial correction by imidapril

We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-beta(1), -gamma(1), and -delta(1) in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6-17% of controls) of the mass and activity of gamma(1)- and delta(1)-isoforms in combination with a significant increase of both PLC beta(1) parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-beta(1), -gamma(1), and -delta(1) occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-β1, -γ1, and -δ1 in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6-17% of controls) of the mass and activity of γ1- and δ1-isoforms in combination with a significant increase of both PLC β1 parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-β1, -γ1, and -δ1 occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.

Myosin light-chain phosphorylation in diabetic cardiomyopathy in rats

The regulatory myosin light chain (MLC) is phosphorylated in cardiac muscle by Ca2+/calmodulin-dependent MLC kinase (MLCK) and is considered to play a modulatory role in the activation of myofibrillar adenosine triphosphatase (ATPase) and the process of force generation. Since the depression in cardiac contractile function in chronic diabetes is associated with a decrease in myofibrillar ATPase activity, we investigated changes in MLC phosphorylation in diabetic heart. Rats were made diabetic by injecting streptozotocin (65 mg/kg intravenously), and the hearts were removed 8 weeks later; some 6-week diabetic animals were injected with insulin (3 U/d) for 2 weeks. Changes in the relative MLC and MLCK protein contents were measured by electrophoresis and immunoblot assay, whereas phosphorylated and unphosphorylated MLCs were separated on 10% acrylamide/urea gel and identified by Western blot. MLC and MLCK contents were decreased markedly (40% to 45%) and MLC phosphorylation was decreased significantly (30% to 45%) in the diabetic rat heart homogenate in comparison to control values. The changes in MLC and MLCK content in diabetic heart were partially reversible, whereas changes in MLC phosphorylation were normalized upon treatment with insulin. These results suggest that decreased protein contents of MLC and MLCK and phosphorylation of MLC may contribute to the depression of cardiac myofibriliar ATPase activity and heart dysfunction in diabetic cardiomyopathy.

Alterations of sarcolemmal phospholipase D and phosphatidate phosphohydrolase in congestive heart failure.

Phospholipase D 2 (PLD2) is the major PLD isozyme associated with the cardiac sarcolemmal (SL) membrane. Hydrolysis of SL phosphatidylcholine (PC) by PLD2 produces phosphatidic acid (PA), which is then converted to 1,2 diacylglycerol (DAG) by the action of phosphatidate phosphohydrolase type 2 (PAP2). In view of the role of both PA and DAG in the regulation of Ca(2+) movements and the association of abnormal Ca(2+) homeostasis with congestive heart failure (CHF), we examined the status of both PLD2 and PAP2 in SL membranes in the infarcted heart upon occluding the left coronary artery in rats for 1, 2, 4, 8 and 16 weeks. A time-dependent increase in both SL PLD2 and PAP2 activities was observed in the non-infarcted left ventricular tissue following myocardial infarction (MI); however, the increase in PAP2 activity was greater than that in PLD2 activity. Furthermore, the contents of both PA and PC were reduced, whereas that of DAG was increased in the failing heart SL membrane. Treatment of the CHF animals with imidapril, an angiotensin-converting enzyme (ACE) inhibitor, attenuated the observed changes in heart function, SL PLD2 and PAP2 activities, as well as SL PA, PC and DAG contents. The results suggest that heart failure is associated with increased activities of both PLD2 and PAP2 in the SL membrane and the beneficial effect of imidapril on heart function may be due to its ability to prevent these changes in the phospholipid signaling molecules in the cardiac SL membrane.

Remodelling of Subcellular Organelles During the Development of Diabetic Cardiomyopathy

In view of the fact that cardiac contractile force development is a cellular event, much data have accumulated in the literature to support a close association between changes in the intracellular concentration of calcium and the status of heart function. Accordingly, mechanisms which regulate calcium homeostasis in the cell and components which interact with calcium are considered important determinants of the heart function. Several organelles such as the sarcolemmal membrane, the sarcoplasmic reticulum (SR), the mitochondria, and the contractile proteins in the myocardial cell are involved in the control of intracellular calcium, contractile force generation and relaxation in the heart. Since these organelles are important for the viability of the healthy myocardium, it is reasonable to assume that a lesion in one or more of these organelles may be associated with a depression of cardiac function commonly observed in chronic diabetes. The possibility that functional abnormalities associated with diabetes mellitus may result from significant remodelling of various organelles has been addressed by a number of laboratories.

Sarpogrelate Inhibits Genes Involved in Vascular Neointimal Hyperplasia and Remodeling

Although basic molecular mechanisms of vascular neointimal hyperplasia leading to vascular remodeling remain unknown, it is generally held that various genes are upregu-lated or inhibited during this process. We have recently discovered that a specific serotonin receptor (5-HT2A) antagonist, sarpogrelate, inhibits vascular remodeling by suppressing the serotonin-induced c-fos and c-jun heterodimerization. By conducting RT-PCR and cell transfection studies, we have shown that over-expression of the 5-HT2A receptor enhanced while sarpogrelate inhibited vascular neoinitmal hyperplasia and remodeling by binding with the ligand binding domain (localized in the third intra-cytoplasmic loop) of the 5-HT2A receptor. These data are interpreted to suggest the therapeutic potential of sarpogrelate in cardiovascular diseases such as atherosclerosis, myocardial ischemia, and coronary artery restenosis.

The Ischemic Heart

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β-Adrenergic Receptor Mechanisms in Heart Failure

In order to explain the attenuated responses of failing hearts to catecholamines, several investigators have attempted to examine the status of β -adrenoceptors by using different experimental models of heart failure as well as in myocardial tissue from patients with heart failure. Conflicting results from different laboratories appear to be due to the stage and type of heart failure. Congestive heart failure due to myocardial infarction in rats exhibited a decrease in the density of β -adrenergic receptors in failing left ventricles, whereas no changes were observed in the hypertrophied right ventricle; these data suggest that the reduced number of β -adrenergic receptors commonly seen in the failing hearts is not due to cardiac hypertrophy per se. Although elevated levels of plasma catecholamines in heart failure are usually considered to result in desensitization of β -adrenoceptors in failing hearts, other different mechanisms, incluing some of local nature, cannot be excluded.

Molecular biologic Changes of Adenine Nucleotide Translocator in J-2-N Cardiomyopathic Hamsters

The adenine nucleotide translocator (ANT) is an integral protein present in the inner mitochondrial membrane that performs the exchange of cytoplasmic and intramitochondrial ADP and ATP. The ANT content of the myocardium was studied in J-2-N cardiomyopathic hamsters. The ANT content was significantly decreased in J-2-N hamsters. By molecular biologic analysis, hamster ANT cDNA of the Tl isoenzyme was cloned by the plaque hybridization method. The ANT cDNA hybridized specifically with ANT mRNA, so RNA dot-blot hybridization was performed. The highest ANT mRNA level was observed in control hamsters followed by J-2-N hamsters with mild myocardial damage, J-2-N hamsters with severe myocardial damage, and Bio 14.6 cardiomyopathic hamsters. These results suggest that a decreased ANT content may contribute to the pathogenesis of cardiomyopathy and that a decrease in ANT mRNA levels may explain the abnormalities of ANT in J-2-N cardiomyopathic hamsters.