Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels.

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.

Being present and thankful: A multi-study investigation of mindfulness, gratitude, and employee helping behavior.

Gratitude plays an integral role in promoting helping behavior at work. Thus, cultivating employees' experiences of gratitude represents an important imperative in modern organizations that rely on teamwork and collaboration to achieve organizational goals. Yet, today's workplace presents a complex array of demands that make it difficult for employees to fully attend to and appreciate the various benefits they receive at work. As such, gratitude is difficult for employers to promote and for employees to experience. Despite these observations, the role of attention and awareness in facilitating employees' feelings of gratitude is largely overlooked in the extant literature. In this study, we examined whether one notable form of present moment attention, mindfulness, may promote helping behavior by stimulating the positive, other-oriented emotion of gratitude. Across two experimental studies, a semiweekly, multisource diary study, and a 10-day experience sampling investigation, we found converging evidence for a serial mediation model in which state mindfulness, via positive affect and perspective taking, prompts greater levels of gratitude, prosocial motivation, and, in turn, helping behavior at work. We discuss the theoretical and practical implications of our investigation, as well as avenues for the future research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Proteomic profiling of concurrently isolated primary microvascular endothelial cells, pericytes, and vascular smooth muscle cells from adult mouse heart.

The microcirculation serves crucial functions in adult heart, distinct from those carried out by epicardial vessels. Microvessels are governed by unique regulatory mechanisms, impairment of which leads to microvessel-specific pathology. There are few treatment options for patients with microvascular heart disease, primarily due to limited understanding of underlying pathology. High throughput mRNA sequencing and protein expression profiling in specific cells can improve our understanding of microvessel biology and disease at the molecular level. Understanding responses of individual microvascular cells to the same physiological or pathophysiological stimuli requires the ability to isolate the specific cell types that comprise the functional units of the microcirculation in the heart, preferably from the same heart, to ensure that different cells have been exposed to the same in-vivo conditions. We developed an integrated process for simultaneous isolation and culture of the main cell types comprising the microcirculation in adult mouse heart: endothelial cells, pericytes, and vascular smooth muscle cells. These cell types were characterized with isobaric labeling quantitative proteomics and mRNA sequencing. We defined microvascular cell proteomes, identified novel protein markers, and confirmed established cell-specific markers. Our results allow identification of unique markers and regulatory proteins that govern microvascular physiology and pathology.

Phosphoproteomic response of cardiac endothelial cells to ischemia and ultrasound.

Myocardial infarction and subsequent therapeutic interventions activate numerous intracellular cascades in every constituent cell type of the heart. Endothelial cells produce several protective compounds in response to therapeutic ultrasound, under both normoxic and ischemic conditions. How endothelial cells sense ultrasound and convert it to a beneficial biological response is not known. We adopted a global, unbiased phosphoproteomics approach aimed at understanding how endothelial cells respond to ultrasound. Here, we use primary cardiac endothelial cells to explore the cellular signaling events underlying the response to ischemia-like cellular injury and ultrasound exposure in vitro. Enriched phosphopeptides were analyzed with a high mass accuracy liquid chromatrography (LC) - tandem mass spectrometry (MS/MS) proteomic platform, yielding multiple alterations in both total protein levels and phosphorylation events in response to ischemic injury and ultrasound. Application of pathway algorithms reveals numerous protein networks recruited in response to ultrasound including those regulating RNA splicing, cell-cell interactions and cytoskeletal organization. Our dataset also permits the informatic prediction of potential kinases responsible for the modifications detected. Taken together, our findings begin to reveal the endothelial proteomic response to ultrasound and suggest potential targets for future studies of the protective effects of ultrasound in the ischemic heart.

(Phospho)Proteomic dataset of ischemia- and ultrasound- stimulated mouse cardiac endothelial cells in vitro.

Cardiac endothelial cells respond to both ischemia and therapeutic ultrasound; the proteomic changes underlying these responses are unknown. This data article provides raw and processed data resulting from our global, unbiased phosphoproteomics investigation conducted on primary mouse cardiac endothelial cells exposed to ischemia (2-hour oxygen glucose deprivation) and ultrasound (250 kHz, 1.2 MPa) in vitro [1]. Proteins were extracted from cell lysates and enriched phosphopeptides were analyzed with a high mass accuracy liquid chromatrography (LC) - tandem mass spectrometry (MS/MS) proteomic platform, yielding multiple alterations in both total protein levels and phosphorylation events in response to ischemic injury and ultrasound. This dataset can be used as a reference for future studies on the cardiac endothelial response to ischemia and the mechanistic underpinnings of the cellular response to ultrasound, with the potential to yield clinically relevant therapeutic targets.

The Moderating Effect of Psychological Contract Violation on the Relationship between Narcissism and Outcomes: An Application of Trait Activation Theory.

We use trait activation and psychological contracts theories to build the argument that narcissism is a personality trait that will manifest itself in the form of exit and neglect when employees experience psychological contract violation. To test our hypotheses, we surveyed 262 employees from a wide array of industries working in different organizations at two points in time. Our results indicate that violation moderated the relationship between narcissism and exit such that narcissistic employees who experienced high levels of violation had higher levels of exit. However, we did not find support for our prediction regarding neglect. The findings suggest that the importance of narcissism at work may be contingent on the situation. Our study contributes to research on narcissism in the workplace, trait activation theory, and the role that individual differences play in shaping employee responses to psychological contract violation.

The moderating roles of self-esteem and neuroticism in the relationship between group and individual undermining behavior.

The authors developed and tested a multilevel interactive model of the relationship between group undermining and individual undermining behavior in 2 multiwave studies of group members. Integrating the literature on group influences on individual behavior with the individual difference literature, the authors predicted a 3-way Group Undermining x Self-Esteem x Neuroticism interaction, such that the relationship between group and individual undermining would be strongest among those simultaneously high in self-esteem and neuroticism. The 3-way interaction was supported in Study 1 (457 participants in 103 groups) and replicated in Study 2 (415 participants in 93 groups) with additional controls and alternative measures of key constructs. The authors discuss the implications of the research and identify future research directions.

Roots run deep: Investigating psychological mechanisms between history of family aggression and abusive supervision.

In this article, we examine the relationships between supervisor-level factors and abusive supervision. Drawing from social learning theory (Bandura, 1973), we argue that supervisors' history of family aggression indirectly impacts abusive supervision via both hostile cognitions and hostile affect, with angry rumination functioning as a first-stage moderator. Using multisource data, we tested the proposed relationships in a series of 4 studies, each providing evidence of constructive replication. In Study 1, we found positive relationships between supervisors' history of family aggression, hostile affect, explicit hostile cognitions, and abusive supervision. We obtained the same pattern of results in Studies 2, 3, and 4 using an implicit measure of hostile cognitions and controlling for previously established antecedents of abusive supervision. Angry rumination moderated the indirect relationship between supervisors' history of family aggression and abusive supervision via hostile affect only. Overall, the results highlight the important role of supervisor-level factors in the abusive supervision dynamics.

A social exchange-based model of the antecedents of workplace exclusion.

We conducted 2 studies of coworker dyads to test a theoretical model exploring why and under what circumstances employees are the targets of workplace exclusion. Adopting a victim precipitation perspective, we integrate belongingness and social exchange theories to propose that employees who display workplace incivility are distrusted and therefore are targets of workplace exclusion. Highlighting the importance of the context of the perpetrator-target relationship, we also find support for the postulation that this mediated relationship is strengthened when the target employee is perceived to be a weak exchange partner and is attenuated when he or she is viewed as a valuable exchange partner. Theoretical and practical implications are discussed.

When distress hits home: the role of contextual factors and psychological distress in predicting employees' responses to abusive supervision.

We developed a model of the relationships among aggressive norms, abusive supervision, psychological distress, family undermining, and supervisor-directed deviance. We tested the model in 2 studies using multisource data: a 3-wave investigation of 184 full-time employees (Study 1) and a 2-wave investigation of 188 restaurant workers (Study 2). Results revealed that (a) abusive supervision mediated the relationship between aggressive norms and psychological distress, (b) psychological distress mediated the effects of abusive supervision on spouse undermining, (c) abusive supervision had a direct positive relationship with supervisor-directed deviance, (d) the positive relationship between psychological distress and spouse undermining was stronger for men as opposed to women, and (e) employees engaged in relationship-oriented occupations reported greater levels of abusive supervision and psychological distress. Implications for theory and practice are discussed.

A contingency model of conflict and team effectiveness.

The authors develop and test theoretical extensions of the relationships of task conflict, relationship conflict, and 2 dimensions of team effectiveness (performance and team-member satisfaction) among 2 samples of work teams in Taiwan and Indonesia. Findings show that relationship conflict moderates the task conflict-team performance relationship. Specifically, the relationship is curvilinear in the shape of an inverted U when relationship conflict is low, but the relationship is linear and negative when relationship conflict is high. The results for team-member satisfaction are more equivocal, but the findings provide some evidence that relationship conflict exacerbates the negative relationship between task conflict and team-member satisfaction.