Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

Signal transducer and activator of transcription 3 (STAT3) protects the heart from acute ischemic stress. However, the importance of STAT3 to the heart in chronic stress, such as hypertension, is not known. To study this, we used cardiomyocyte-targeted STAT3 knockout (KO) mice and ANG II infusion by osmotic minipumps. After 4 weeks, ANG II induced similar cardiac hypertrophy in wild type (WT) and cardiac Cre-expressing control (CTRL) mice with no impairment of cardiac function. In contrast, STAT3 KO mice exhibited reduced contractile function but similar hypertrophy to CTRL mice. Ejection fraction and fractional shortening decreased by 22.5% and 27.3%, respectively. Since STAT3 has direct protective effects on mitochondrial function, we examined rates of glucose and oleate oxidation by isolated perfused hearts using a Langendorff system. Hearts of ANG II-treated STAT3 KO and CTRL mice had similar rates of oleate oxidation as saline-infused WT mice. Rates of glucose oxidation were similar between hearts of WT plus saline and CTRL plus ANG II mice; however, glucose oxidation was increased by 66% in hearts of ANG II-treated STAT3 KO mice. The ratio of maximal ATP yield from glucose to fatty acid oxidation was 21.1 ± 3.1 in hearts of ANG II-treated STAT3 KO mice vs. 12.6 ± 2.2 in hearts of ANG II-treated CTRL mice. Lactate production was also elevated in hearts of ANG II-treated STAT3 KO mice by 162% compared to ANG II-treated CTRL mice. Our findings indicate that (1) STAT3 is important for maintaining contractile function and metabolic homeostasis in the hypertensive heart, and (2) STAT3 deficiency promotes a switch toward glucose utilization

Master of Science

thesisAlthough many studies have examined acoustic and sociolinguistic differences between male and female speech, the relationship between talker speaking style and perceived gender has not yet been explored. The present study attempts to determine whether clear speech, a style adopted by talkers who perceive some barrier to effective communication, shifts perceptions of femininity for male and female talkers

Successful new product development by optimizing development process effectiveness in highly regulated sectors: the case of the Spanish medical devices sector

Rapid development and commercialization of new products is of vital importance for small and medium sized enterprises (SME) in regulated sectors. Due to strict regulations, competitive advantage can hardly be achieved through the effectiveness of product concepts only. If an SME in a highly regulated sector wants to excell in new product development (NPD) performance, the company should focus on the flexibility, speed, and productivity of its NPD function: i.e. the development process effectiveness. Our main research goals are first to explore if SMEs should focus on their their development process effectiveness rather than on their product concept effectiveness to achieve high NPD performance; and second, to explore whether a shared pattern in the organization of the NPD function can be recognized to affect NPD performance positively. The medical devices sector in Spain is used as an example of a\ud highly regulated sector. A structured survey among 11 SMEs, of which 2 were studied also as in in-depth case studies, led to the following results. First of all, indeed the companies in the dataset which focused on the effectiveness of their development process, stood out in NPD performance. Further, the higher performing companies did have a number of commonalities in the organisation of their NPD function: 1) The majority of the higher performing firms had an NPD strategy characterized by a predominantly incremental project portfolio.\ud 2) a) Successful firms with an incremental project portfolio combined this with a functional team structure b) Successful firms with a radical project portfolio combined this with a heavyweight or autonomous team structure.\ud 3) A negative reciprocal relationship exists between formalization of the NPD processes and the climate of the NPD function, in that a formalized NPD process and an innovative climate do not seem to reinforce each other. Innovative climate combined with an informal NPD process does however contribute positively to NPD performance. This effect was stronger in combination with a radical project portfolio. The highest NPD performance was measured for companies focusing mainly on incremental innovation. It is argued that in highly regulated sectors, companies with an incremental product portfolio would benefit from employing a functional structure. Those companies who choose for a more radical project portfolio in highly regulated sectors should be aware\ud that they are likely to excell only in the longer term by focusing on strategic flexibility. In their NPD organization, they might be well advised to combine informal innovation processes with an innovative climate

Angiotensin-(1-7) and angiotensin-(1-9): function in cardiac and vascular remodeling

The renin angiotensin system (RAS) is integral to cardiovascular physiology, however, dysregulation of this system largely contributes to the pathophysiology of cardiovascular disease (CVD). It is well established that angiotensin II (Ang II), the main effector of the RAS, engages the angiotensin type 1 receptor and promotes cell growth, proliferation, migration and oxidative stress, all processes which contribute to remodeling of the heart and vasculature, ultimately leading to the development and progression of various CVDs including heart failure and atherosclerosis. The counter-regulatory axis of the RAS, which is centered on the actions of angiotensin converting enzyme 2 (ACE2) and the resultant production of angiotensin-(1-7) (Ang-(1-7) from Ang II, antagonizes the actions of Ang II via the receptor Mas, thereby providing a protective role in CVD. More recently, another ACE2 metabolite, Ang-(1-9), has been reported to be a biologically active peptide within the counter-regulatory axis of the RAS. This review will discuss the role of the counter-regulatory RAS peptides, Ang-(1-7) and Ang-(1-9) in the cardiovascular system, with a focus on their effects in remodeling of the heart and vasculature

The Ependyma of the Cat Central Canal, with Particular Reference to its Mitochondria-Containing Bulbs

The ultrastructure of the ependyma in the central canal of adult cats was examined in both the scanning and the transmission electron microscopes (SEM and TEM). The same morphological details were seen in the ependyma of the central canal as have so frequently been described in the ependyma of the brain ventricular system, for example bundles of cilia, single cilia, microvilli and occasional small cytoplasmic protrusions. The supraependymal cells and supraependymal nerve fibers found in the central canal also resembled those seen in the ventricular system. The most striking feature of the canal ependyma were the large, spherical bodies containing numerous mitochondria. They are therefore called mitochondria-containing bulbs. In sections the bulbs were seen to be connected by long, slender stalks to neurons in subependymal position. In some respects the mitochondria-containing bulbs resemble the processes of cerebrospinal fluid-contacting neurons

The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart.

Accumulating evidence reveals involvement of T lymphocytes and adaptive immunity in the chronic inflammation associated with infectious and noninfectious diseases of the heart, including coronary artery disease, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, hypertensive left ventricular (LV) hypertrophy, and nonischemic heart failure. Chemokine CXCL10 is elevated in cardiovascular diseases, along with increased cardiac infiltration of proinflammatory Th1 and cytotoxic T cells. CXCL10 is a chemoattractant for these T cells and polarizing factor for the proinflammatory phenotype. Thus, targeting the CXCL10 receptor CXCR3 is a promising therapeutic approach to treating cardiac inflammation. Due to biased signaling CXCR3 also couples to anti-inflammatory signaling and immunosuppressive regulatory T cell formation when activated by CXCL11. Numbers and functionality of regulatory T cells are reduced in patients with cardiac inflammation, supporting the utility of biased agonists or biologicals to simultaneously block the pro-inflammatory and activate the anti-inflammatory actions of CXCR3. Other immunotherapy strategies to boost regulatory T cell actions include intravenous immunoglobulin (IVIG) therapy, adoptive transfer, immunoadsorption, and low-dose interleukin-2/interleukin-2 antibody complexes. Pharmacological approaches include sphingosine 1-phosphate receptor 1 agonists and vitamin D supplementation. A combined strategy of switching CXCR3 signaling from pro- to anti-inflammatory and improving Treg functionality is predicted to synergistically lessen adverse cardiac remodeling

Technology transfer offices as boundary spanners in the pre-spin-off process: the case of a hybrid model

Over the past decades, universities have increasingly become ambidextrous organizations reconciling scientific and commercial missions. In order to manage this ambidexterity, technology transfer offices (TTOs) were established in most universities. This paper studies a specific, often implemented, but rather understudied type of TTO, namely a hybrid TTO model uniting centralized and decentralized levels. Employing a qualitative research design, we examine how and why the two TTO levels engage in diverse boundary spanning activities to help nascent spin-off companies move through the pre-spin-off process. Our research identifies differences in the types of boundary spanning activities that centralized and decentralized TTOs perform and in the parties they engage with. We find geographical, technological and organizational proximity to be important antecedents of the TTOs’ engagement in external and internal boundary spanning activities. These results have important implications for both academics and practitioners interested in university technology transfer through spin-off creation

Conflicting vascular and metabolic impact of the IL-33/sST2 axis.

Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases

Targeting mitochondria to protect the heart: A matter of balance?

Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species (ROS), as well as apoptosis. Blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In a groundbreaking study appearing in Clinical Science, Maneechote et al. assessed whether correcting the imbalance in mitochondrial dynamics with I/R by enhancing fusion would also be protective. Using a rat model, they investigated the efficacy of pharmacological intervention with mitochondrial fusion promoter-M1 (M1) given before ischemia, during ischemia, or at the onset of reperfusion. With pretreatment being the most effective, they found that M1 attenuated the incidence of arrhythmias, reduced infarct size, preserved cardiac function, and decreased mortality. M1 reduced I/R-induced increases in cytosolic cytochrome c, cleaved caspase 3, and apoptosis. All M1 groups exhibited modestly attenuated I/R-induced mitochondrial ROS levels and swelling, and preserved mitochondrial membrane potential. M1 also prevented a decrease in complex V levels with I/R. However, exactly how M1 stimulates mitochondrial fusion is unclear and other nonfusion-related actions of this phenylhydrazone compound should be considered, such as anti-oxidant actions, preconditioning signaling, or effects on putative mitochondrial connexin 43. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

Unravelling the impact of intrauterine growth restriction on heart development: Insights into mitochondria and sexual dimorphism from a non-hominoid primate

Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei-mitochondria crosstalk with in utero stress awaits further investigation. ©2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society