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Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Elevated galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin-3 levels and myocardial indices of systolic HF. We measured plasma galectin-3 in 133 chronic HF and 45 advanced decompensated HF subjects with echocardiographic and hemodynamic evaluation. In our chronic HF cohort, median plasma galectin-3 level was 13.9ng/mL [interquartile range: 12.1–16.9ng/mL]. Higher galectin-3 was associated with more advanced age (r=0.22, p=0.010) and poor renal function (estimated glomerular filtration rate [eGFR]: r= −0.24, p=0.007; cystatin C: r= 0.38, p<0.0001), and predicted all-cause mortality (Hazard ratio [HR] 1.86 [95% confidence interval: 1.36–2.54], p<0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, eGFR, left ventricular (LV) ejection fraction (EF), and mitral E/septal Ea (HR 1.94 [1.30–2.91], p=0.001). However, galectin-3 did not predict the combined endpoint of all-cause mortality, cardiac transplantation, or HF hospitalization (p>0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r= −0.05, p=0.61), LVEF (r= 0.10, p=0.25), or LV diastolic function (mitral E/septal Ea: r= 0.06, p=0.52; left atrial volume index: r= 0.08, p=0.41). In our advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indices. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indices.

Death-associated protein kinase (DAPK) is a multidomain Ser/Thr protein kinase with an important role in apoptosis regulation. In these studies we have identified a DAPK-interacting protein called DIP-1, which is a novel multi-RING finger protein. The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system. Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation.Regulation of protein degradation by the ubiquitin proteasome pathway is now known to be a major pathway through which cells modulate the expression levels of critical signaling proteins (1-6). This tightly regulated, complex pathway is a key regulator of many important signaling pathways and has an important role in many cellular processes including apoptosis, and recent studies have identified many apoptosis regulatory proteins as targets for ubiquitination (7-11). In addition to being targets for degradation, some apoptosis regulatory proteins have a more active role and act as components of the ubiquitin cascade via the ubiquitin ligase activity ascribed to the RING finger domains that is part of their primary structure. Targeting proteins for degradation by the ubiquitin proteasome pathway involves the covalent linkage of ubiquitin either to the amino terminus or specific lysine residues in the target protein through the action of three enzymes. In this process ubiquitin is first activated by an E1 ubiquitin-activating enzyme, transferred to an E2 ubiquitin-conjugating enzyme, and then ligated to the target protein by an E3 ubiquitin ligase (4,12) Recently the Ser/Thr protein kinase, death-associated protein kinase (DAPK) 1 has been implicated in apoptosis regulation. DAPK has a complex, multi-domain structure that includes a calcium/calmodulin-regulated kinase domain, a series of ankyrin repeats, and a carboxyl-terminal death domain (13-17). Although some of the regulatory features that directly control the catalytic activities of DAPK have been described, including the activation by calcium/calmodulin (17, 18) and the presence of an inhibitory autophosphorylation site (19), an understanding of how the cellular activities of DAPK are regulated in vivo is poorly understood. The presence of proteinprotein interaction domains within the primary structure of DAPK, including its ankyrin repeat motifs and death domain, suggests that additional interactions between DAPK and other cellular proteins will also be important for regulation of DAPK activities. In this study, we describe a new DAPK-interacting protein called DIP-1 (DAPK-interacting protein-1), which has a direct role in r...

Abstract-Akt is a central regulator of cardiomyocyte survival after ischemic injury in vitro and in vivo, but the mechanisms regulating Akt activity in the postischemic cardiomyocyte are not known. Furthermore, although much is known about the detrimental role that the c-Jun N-terminal kinases (JNKs) play in promoting death of cells exposed to various stresses, little is known of the molecular mechanisms by which JNK activation can be protective. We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase. The reduction in Akt activity that is induced by JNK inhibition may have significant biological consequences, as we find that JNKs, acting via Akt, are critical determinants of survival in posthypoxic cardiomyocytes in culture. Furthermore, in contrast to selective p38 -mitogen-activated protein kinase inhibition, which was cardioprotective in vivo, concurrent inhibition of both JNKs and p38 -mitogen-activated protein kinases increased ischemia/reperfusion injury in the heart of the intact rat. These studies demonstrate that reactivation of Akt after resolution of hypoxia and ischemia is regulated by JNKs and suggest that this is likely a central mechanism of the myocyte protective effect of JNKs. (Circ Res. 2006;98:111-118.)Key Words: Akt Ⅲ apoptosis Ⅲ c-Jun NH2-terminal kinase Ⅲ hypoxia Ⅲ ischemia Ⅲ signal transduction T he families of stress-activated protein kinases (SAPKs) consist of the c-Jun N-terminal kinase (JNK) family and the p38 -mitogen-activated protein kinase (MAPK) family. 1 They are potently activated by a number of cellular stresses and produce a number of biological responses that vary by the stimulus and the cell type. These kinases are activated by ischemia (especially p38-MAPKs 2 ) and by reperfusion of ischemic tissues (JNKs and to a lesser extent p38-MAPKs 3 ).Recently, a potent and relatively selective inhibitor of the ␣ and ␤ p38-MAPK isoforms has demonstrated reductions in ischemic injury in animal models of myocardial infarction and stroke. 4,5 In addition, overexpression of dominant negative mutants of components of the p38-MAPK pathway in transgenic mice protected hearts from ischemia/reperfusion (I/R) injury. 6 However, the roles played by the JNKs in ischemic injury are much less clear than those of p38-MAPKs. This is due in large part to the fact that potent and selective inhibitors of the JNKs have only very recently been developed, are not widely available, and, to our knowledge, have not been used to study I/R injury either in vivo or in cultured cardiomyocytes.In support of a deleterious role for JNKs in ischemic injury, studies in mice in which the JNK3 gene has been deleted and studies with a peptide inhibitor of JNKs demonstrated markedly reduced ischemic injury and excitotoxicity in th...