Exogenous ubiquitin reduces inflammatory response and preserves myocardial function 3 days post-ischemia-reperfusion injury.

ß-Adrenergic receptor (ß-AR) stimulation increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases ß-AR-stimulated myocyte apoptosis and myocardial fibrosis. Here, we hypothesized that exogenous UB modulates the inflammatory response, thereby playing a protective role in cardiac remodeling after ischemia-reperfusion (I/R) injury. C57BL/6 mice infused with vehicle or UB (1 µg·g-1·h-1) were subjected to myocardial I/R injury. Functional and biochemical parameters of the heart were examined 3 days post-I/R. Heart weight-to-body weight ratios were similarly increased in I/R and UB + I/R groups. The area at risk and infarct size were significantly lower in UB + I/R versus I/R groups. Measurement of heart function using echocardiography revealed that I/R decreases percent fractional shortening and percent ejection fraction. However, the decrease in fractional shortening and ejection fraction was significantly lower in the UB + I/R group. The UB + I/R group displayed a significant decrease in inflammatory infiltrates, neutrophils, and macrophages versus the I/R group. Neutrophil activity was significantly lower in the UB + I/R group. Analysis of the concentration of a panel of 23 cytokines/chemokines in the serum using a Bio-Plex assay revealed a significantly lower concentration of IL-12 subunit p40 in the UB + I/R versus I/R group. The concentration of monocyte chemotactic protein-1 was lower, whereas the concentration of macrophage inflammatory protein-1α was significantly higher, in the UB+I/R group versus the sham group. Expression of matrix metalloproteinase (MMP)-2 and activity of MMP-9 were higher in the UB + I/R group versus the I/R group. Levels of ubiquitinated proteins and tissue inhibitor of metalloproteinase 2 expression were increased to a similar extent in both I/R groups. Thus, exogenous UB plays a protective role in myocardial remodeling post-I/R with effects on cardiac function, area at risk/infarct size, the inflammatory response, levels of serum cytokines/chemokines, and MMP expression and activity. NEW & NOTEWORTHY Stimulation of ß-adrenergic receptors increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases ß-adrenergic receptor-stimulated myocyte apoptosis and myocardial fibrosis. Here, we provide evidence that exogenous UB decreases the inflammatory response and preserves heart function 3 days after myocardial ischemia-reperfusion injury. Further identification of the molecular events involved in the anti-inflammatory role of exogenous UB may provide therapeutic targets for patients with ischemic heart disease.

Ataxia telangiectasia mutated kinase deficiency impairs the autophagic response early during myocardial infarction.

Ataxia telangiectasia mutated kinase (ATM) is activated in response to DNA damage. We have previously shown that ATM plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we tested the hypothesis that ATM deficiency results in autophagic impairment in the heart early during MI. MI was induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Structural and biochemical parameters of the heart were measured 4 h after left anterior descending artery ligation. M-mode echocardiography revealed that MI worsens heart function, as evidenced by reduced percent ejection fraction and fractional shortening in both groups. However, MI-induced increase in left ventricular end-diastolic and end-systolic diameters and volumes were significantly lower in hKO hearts. ATM deficiency resulted in autophagic impairment during MI, as evidenced by decreased microtubule-associated protein light chain 3-II increased p62, decreased cathepsin D protein levels, and increased aggresome accumulation. ERK1/2 activation was only observed in WT-MI hearts. Activation of Akt and AMP-activated protein kinase (AMPK) was lower, whereas activation of glycogen synthase kinase (GSK)-3ß and mammalian target of rapamycin (mTOR) was higher in hKO-MI hearts. Inhibition of ATM using KU-55933 resulted in autophagic impairment in cardiac fibroblasts, as evidenced by decreased light chain 3-II protein levels and formation of acidic vesicular organelles. This impairment was associated with decreased activation of Akt and AMPK but enhanced activation of GSK-3ß and mTOR in KU-55933-treated fibroblasts. Thus, ATM deficiency results in autophagic impairment in the heart during MI and cardiac fibroblasts. This autophagic impairment may occur via the activation of GSK-3ß and mTOR and inactivation of Akt and AMPK. NEW & NOTEWORTHY Ataxia telangiectasia mutated kinase (ATM) plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we provide evidence that ATM deficiency results in autophagic impairment during MI. Further investigation of the role of ATM in autophagy post-MI may provide novel therapeutic targets for patients with ataxia telangiectasia suffering from heart disease.

Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction.

Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1-7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3ß (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy.

Ataxia-Telangiectasia Mutated Kinase: Role in Myocardial Remodeling.

Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease. However, they are predisposed to developing cancer or ischemic heart disease, and die 7-8 years earlier than the non-carriers. DNA double-strand breaks activate ATM, and active ATM is known to phosphorylate an extensive array of proteins involved in cell cycle arrest, DNA repair, and apoptosis. The importance of ATM in the regulation of DNA damage response signaling is fairly well-established. This review summarizes the role of ATM in the heart, specifically in cardiac remodeling following ß-adrenergic receptor stimulation and myocardial infarction.

Population-Level Density Dependence Influences the Origin and Maintenance of Parental Care.

Parental care is a defining feature of animal breeding systems. We now know that both basic life-history characteristics and ecological factors influence the evolution of care. However, relatively little is known about how these factors interact to influence the origin and maintenance of care. Here, we expand upon previous work and explore the relationship between basic life-history characteristics (stage-specific rates of mortality and maturation) and the fitness benefits associated with the origin and the maintenance of parental care for two broad ecological scenarios: the scenario in which egg survival is density dependent and the case in which adult survival is density dependent. Our findings suggest that high offspring need is likely critical in driving the origin, but not the maintenance, of parental care regardless of whether density dependence acts on egg or adult survival. In general, parental care is more likely to result in greater fitness benefits when baseline adult mortality is low if 1) egg survival is density dependent or 2) adult mortality is density dependent and mutant density is relatively high. When density dependence acts on egg mortality, low rates of egg maturation and high egg densities are less likely to lead to strong fitness benefits of care. However, when density dependence acts on adult mortality, high levels of egg maturation and increasing adult densities are less likely to maintain care. Juvenile survival has relatively little, if any, effect on the origin and maintenance of egg-only care. More generally, our results suggest that the evolution of parental care will be influenced by an organism's entire life history characteristics, the stage at which density dependence acts, and whether care is originating or being maintained.