Possible therapeutic targets in cardiac myocyte apoptosis.

Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, angiotensin converting enzyme inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.

Molecular mechanisms of apoptosis in the cardiac myocyte.

Cardiac myocytes can undergo programmed cell death in response to a variety of insults and apoptotic elimination of myocytes from the adult myocardium can lead directly to cardiomyopathy and death. Although it remains to be shown that therapy specifically targeting apoptosis will improve the prognosis of ischemic heart disease or heart failure, a number of studies in the past year have shed light on potential ways to intervene in the process. Progress in the past year includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, nitric oxide and calcineurin. Further evidence supports the pathophysiologic relevance of apoptosis in human heart disease. The tracking of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein (MAP) kinases p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminus kinase (JNK) in cardiac cell fate.

[Molecular regulation of myocardial apoptosis]. / A szívizom apoptosisának molekuláris szabályozása.

Since apoptosis was described as a process distinct from necrosis, there have been many studies of programmed cell death in diseases, especially immunological diseases. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last six to seven years this view has been challenged by several studies demonstrating that a significant number of myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogen right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially very important observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. The tracking of cytoprotective and apoptotic signal transduction pathways has proceeded rapidly with important new insights into the roles of mitochondria-dependent pathway, Bcl-2 protein family, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase in cell fate. New studies have demonstrated that specific inhibition of apoptosis and activation of cytoprotective mechanisms, based on the better understanding of the intracellular signaling pathways, can significantly protect cardiac myocytes. This review will assess progress in cardiac myocyte apoptosis research and report on the current status of anti-apoptotic therapy in acute and chronic heart diseases.

Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis.

Nitric oxide (NO) induces apoptosis in cardiac myocytes through an oxidant-sensitive mechanism. However, additional factors appear to modulate the exact timing and rate of NO-dependent apoptosis. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] 1/2, and p38MAPK) in NO-mediated apoptotic signaling. The NO donor S:-nitrosoglutathione (GSNO) induced caspase-dependent apoptosis in neonatal rat cardiac myocytes, preceded by a rapid (<10-minute) and significant (approximately 50-fold) activation of JNK1/2. Activation of JNK was cGMP dependent and was inversely related to NO concentration; it was maximal at the lowest dose of GSNO (10 micromol/L) and negligible at 1 mmol/L. NO slightly increased ERK1/2 beginning at 2 hours but did not affect p38MAPK activity. Inhibitors of ERK and p38MAPK activation did not affect cell death rates. In contrast, expression of dominant-negative JNK1 or MKK4 mutants significantly increased NO-induced apoptosis at 5 hours (56.77% and 57.37%, respectively, versus control, 40.5%), whereas MEKK1, an upstream activator of JNK, sharply reduced apoptosis in a JNK-dependent manner. Adenovirus-mediated expression of dominant-negative JNK1 both eliminated the rapid activation of JNK by NO and accelerated NO-mediated apoptosis by approximately 2 hours. These data indicate that NO activates JNK as part of a cytoprotective response, concurrent with initiation of apoptotic signaling. Early, transient activation of JNK serves both to delay and to reduce the total extent of apoptosis in cardiac myocytes.

[The role of myocardial apoptosis in the development of heart failure]. / A myocardialis apoptosis szerepe a szívelégtelenség kialakulásában.

Heart failure can result from a variety of causes, including volume or pressure overload and contractile disturbances of the myocardium. Loss of myocytes is an important mechanism in the development of cardiac failure. In general, myocyte death resulting in progressive deterioration of myocardial function is attributed to necrosis, but recently the involvement of programmed cell death (mainly apoptosis) has been suggested. The authors review the possible role of myocardial apoptosis in developing of heart failure. Subcellular genetic regulatory processes as well as the pharmacological susceptibility of programmed cell death are also discussed. In heart failure, significant amount of cardiac myocytes undergoes apoptosis, that unlike necrosis can be prevented. Specific inhibition of this process could mean a considerable part of cardioprotection after thorough understanding of the underlying cellular mechanisms.

[Management of hepatic encephalopathy]. / A hepaticus encephalopathia kezelése.

Among the general principles of the therapy of hepatic encephalopathy the authors discuss the intensive care of patients, maintenance of their volume and electrolyte balance, treatment of coagulation defect, therapy of gastrointestinal bleeding and portal hypertension, provision of central renal catheter, infection prophylaxis, monitoring of intracranial pressure, and if necessary, respiration and intubation of patients. The study also deals with possibilities of treatment based on the toxic hypothesis and on the theory of neurotransmitters. Attention is paid to the therapy of brain oedema and to the significance of hemodialysis, hemoperfusion, plasmapheresis and hybrid bioartificial liver cell treatment. The authors deal with the indications of glucagon-insulin therapy and emphasize the importance of liver transplantation in the treatment of hepatic encephalopathy.

[Alcoholic liver damage and impaired porphyrin metabolism]. / Az alkoholos májkárosodás és a porphyrinanyagcsere zavara.

The authors review the alcohol-induced acquired defect of the porphyrin metabolism. They think that the free radicals formed during the alcohol metabolism may have an important role in the producing of the enzyme defects and in the accomplishment of the acute attack in the genetic porphyrias. In the first part of the article they summarize the genetic hepatic porphyrias, main symptoms, the therapy and the mechanism of the free radical forming during the alcohol metabolism.