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Abstract-Mammalian sterile 20 -like kinase-1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion. Whether or not Mst1 is also involved in the long-term development of heart failure after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1). The left coronary artery was permanently ligated, and the size of MI was similar between Tg-DN-Mst1 and nontransgenic controls (NTg). After 4 weeks, Mst1 was significantly activated in the remodeling area in NTg, but not in Tg-DN-Mst1. Although left ventricular (LV) enlargement was significantly attenuated in Tg-DN-Mst1 compared with NTg, neither LV weight/body weight nor myocyte cross sectional area was statistically different between Tg-DN-Mst1 and NTg. LV ejection fraction was significantly greater in Tg-DN-Mst1 than in NTg (53 versus 38%, PϽ0.01), whereas LV end-diastolic pressure (6 versus 12 mm Hg, PϽ0.05) and lung weight/body weight (9.8 versus 12.2 PϽ0.05) were significantly smaller in Tg-DN-Mst1 than in NTg. The number of TUNEL-positive myocytes (0.17 versus 0.28%, PϽ0.05) and amount of interstitial fibrosis (5.0 versus 7.1%, PϽ0.05) in the remodeling area were significantly less in Tg-DN-Mst1 than in NTg. Upregulation of matrix metalloproteinase 2 and proinflammatory cytokines was significantly attenuated in Tg-DN-Mst1. These results indicate that endogenous Mst1 plays an important role in mediating cardiac dilation, apoptosis, fibrosis, and cardiac dysfunction, but not cardiac hypertrophy, after MI. Inhibition of Mst1 improves cardiac function without attenuating cardiac hypertrophy. Thus, Mst1 may be an important target of heart failure treatment. Key Words: apoptosis Ⅲ hypertrophy Ⅲ myocardial infarction Ⅲ signal transduction A dverse remodeling after myocardial infarction (MI) has a significant impact on global cardiac function. 1 The presence of a nonfunctional area in left ventricular (LV) myocardium resulting from MI increases mechanical loading in the surviving myocardium and local production of autocrine/paracrine factors, such as angiotensin II and tumor necrosis factor (TNF)-␣, which induce global histopathological changes in the LV myocardium, including hypertrophy, inflammation, apoptosis, and fibrosis. This, in turn, leads to chamber dilation and LV dysfunction. 2 Although the signaling mechanisms involved in this process have been gradually elucidated during the past few years, our knowledge still falls short of the ability to translate observations made in basic research into effective treatment for patients with chronic MI.Mammalian sterile 20 -like kinase 1 (Mst1) is a ubiquitously expressed serine/threonine kinase 3 that belongs to the mammalian sterile 20 -like (STE 20 -like) kinase family. 4 Mst1 is activated not only by environmental stresses and cytokines 5 but also by pathologically relevant stimuli, such as hypoxia/reoxygenation. 6 Mst1 and other STE 20 -like family kinases pla...

Activation of mammalian sterile 20–like kinase 1 (Mst1) by genotoxic compounds is known to stimulate apoptosis in some cell types. The importance of Mst1 in cell death caused by clinically relevant pathologic stimuli is unknown, however. In this study, we show that Mst1 is a prominent myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes and that Mst1 causes cardiac myocyte apoptosis in vitro in a kinase activity–dependent manner. In vivo, cardiac-specific overexpression of Mst1 in transgenic mice results in activation of caspases, increased apoptosis, and dilated cardiomyopathy. Surprisingly, however, Mst1 prevents compensatory cardiac myocyte elongation or hypertrophy despite increased wall stress, thereby obscuring the use of the Frank-Starling mechanism, a fundamental mechanism by which the heart maintains cardiac output in response to increased mechanical load at the single myocyte level. Furthermore, Mst1 is activated by ischemia/reperfusion in the mouse heart in vivo. Suppression of endogenous Mst1 by cardiac-specific overexpression of dominant-negative Mst1 in transgenic mice prevents myocyte death by pathologic insults. These results show that Mst1 works as both an essential initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes, resulting in a previously unrecognized form of cardiomyopathy

Abstract-The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT 1 ) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-␤1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT 1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. There are at least 2 isoforms for Ang II receptors, which are designated as AT 1 and AT 2 , and the AT 1 receptor is further subdivided into AT 1A and AT 1B . It is generally accepted that most of the traditional Ang II functions in the cardiovascular system are attributable to the AT 1 receptor. 3 Angiotensin-converting enzyme (ACE) inhibitors or AT 1 receptor blockers induce the regression or prevent the development of left ventricular (LV) hypertrophy, both in animal models 4 -6 and in hypertensive patients. 7,8 However, it has proved difficult to determine whether the antagonistic effects of ACE inhibitors and AT 1 receptor blockers on Ang II-induced growth promotion or the concomitant systemic hemodynamic effects of these agents underlie their beneficial action with regard to this condition. A non-antihypertensive dose of an ACE inhibitor was shown to reverse LV hypertrophy in aortic banded rats, 9,10 and the antihypertrophic effect of an AT 1 receptor blocker was shown to be greater than that of hydralazine, despite the greater antihypertensive effect of hydralazine, in spontaneously hypertensive rats. 6 These observations suggest that blood pressure reduction alone is not sufficient to prevent target organ damage and that the additional control of local or neurohumoral factors might also be required.An intracellular signaling pathway that includes the Ca 2ϩ -dependent protein phosphatase calcineurin has been shown to underlie cardiac hypertrophy. 11 Calcineurin has also been shown to play a key role in the development of pressure overload-induced cardiac hypertrophy. 12,13 A recent study suggested that calcineurin is involved in the development of cardiac hypertrophy induced by mineralocorticoid excess. 14 Furthermore, treatment of cultured cardiac myocytes with Ang II or phenylephrine results in activation of calcineurin. 15 However, the effect of the cardiac renin-angiotensin system (RAS) on calcineurin ...

This study evaluated the influence of three transferrin family proteins (bovine lactotransferrin, bLf; chicken ovotransferrin, cOf; quail ovotransferrin, qOf) at concentrations ranging from 10 to 50 fig ml -1 on proliferative responses of mouse spleen lymphocytes stimulated by lipopolysaccharide (LPS) and phytohemagglutinin (PHA). The transferrins significantly inhibited both the mitogen-induced proliferation in a dose-dependent manner. Ovotransferrins, especially qOf, had cytotoxicity for the lymphocytes. There is no relationship between iron saturation and inhibitory effect of each transferrin or cytotoxicity of ovotransferrins. All these transferrins bound to CD4 + T-lymphocytes, CD8 + T-lymphocytes and B-lymphocytes, but no transferrin conjugated with PHA. PHA bound to lymphocytes previously incubated with each transferrin. These results indicate that the inhibition of proliferation by the transferrins and the cytoxicity of ovotransferrins are not attributable to a function of iron transport and to inactivation of mitogen, suggesting that the hyporesponsiveness is due to interaction of lymphocytes and/or accessory cells with each transferrin.