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Hindbrain Astrocyte Glucodetectors and Counterregulation
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Richard C. Rogers, David H. McDougal, Gerlinda E. Hermann
While compelling, the data discussed so far concerning astrocyte low glucose detection were collected using indirect methods. Direct physiological study of astrocyte “activation” is difficult since these cells are not electrically excitable cells and produce no obvious electrical signatures of activation as do neuronal or beta cell glucosensors. So, unlike neurons, they cannot be studied with direct electrophysiological methods (Araque et al. 1999). Astrocyte signaling is based on calcium flux (Araque, Carmignoto, and Haydon 2001, Vance, Rogers, and Hermann 2015). Calcium signals can be generated by membrane channel activities, but as in other cell types, transmembrane calcium flux is usually coupled to mass calcium release from storage in the ER via CICR through ER ryanodine channels. However, mass release of calcium from ER storage can also occur through a completely separate but parallel inositol tris-phosphate (IP3) channel. This mechanism for ER calcium release is activated by G-protein receptors coupled to phospholipase C (PLC). When activated by Gq-type receptors (such as the PAR receptor), PLC cleaves the membrane phospholipid PIP2 into diacyl glycerol and IP3. The “wave” of cytoplasmic calcium released from the ER due to membrane receptor signaling initiates a cascade of signal transduction events, most notably vesicle secretion from beta cells and gliotransmission from astrocytes (Satin 2000, Zorec et al. 2012). The ER calcium-ATPase pumps are largely responsible for the restoration of cytoplasmic calcium to low levels after signaling events. Reestablishing the transmembrane and ER to cytoplasm concentration gradients is necessary for renewed calcium signaling. Modulation of the calcium ATPase pump and changes in the rate of removal of cytoplasmic calcium could alter the dynamics of the calcium signal as well (Nett, Oloff, and McCarthy 2002).
The Pathophysiology of Heart Failure with Preserved Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Vishal N. Rao, Kishan S. Parikh
Prolonged myocardial relaxation, along with passive stiffness, is believed to serve as one physiological component of HFpEF (Figure 4.2).13 Delayed or impaired diastolic relaxation results in elevations in ventricular end-diastolic pressures with incremental changes in cardiac filling.13,29–32 The ventricular relaxation delay becomes physiologically apparent under certain vascular loading states30 or at faster heart rates with reduced total diastolic filling time.33 Various mechanisms that prolong myocardial relaxation have been proposed.34 In normal ventricles, calcium removal from the cardiomyocyte cytosol is integral to active relaxation via phospholamban (PLB)-modulated uptake of calcium into the sarcoplasmic reticulum by a calcium-ATPase, calcium extrusion via a sodium-calcium exchanger, mitochondrial calcium uniport, and sarcolemmal calcium-ATPase.34,35 In HFpEF, cytosolic calcium is incompletely removed and the sarcoplasmic reticulum stores of calcium for the next systolic cycle are reduced due to calcium-ATPase inactivity (SERCA2a), likely due to reduced protein expression and by reduced phosphorylation of its inhibitory modulating protein. Active relaxation is further reduced in HFpEF due to downregulation of beta-adrenergic receptor expression36 and depressed responsiveness,37 contributing to signaling irregularities and downstream myocardial changes. Furthermore, the myofilament titin and other elastic elements and their restoring forces facilitate sarcomere movement toward resting length in diastole as well as in the regulation of calcium activation/deactivation during the cardiac cycle, so that reduced levels of titin may contribute to the diastolic dysfunction and reduced myocardial efficiency in HFpEF.38
Biochemistry of Exercise Training and Mitigation of Cardiovascular Disease
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Barry A. Franklin, John C. Quindry
The fact that metabolic activity in exercised hearts is improved during an ischemic challenge suggests that calcium handling is also improved and oxidative stress is mitigated. Indeed, strong evidence indicates that exercise pre-conditioning preserves calcium control during ischemia (20), although the protection is attenuated when compared with the unstressed heart (141). Preservation of cellular calcium transients is at least modestly improved by the fact that the sarcoplasmic endoplasmic calcium ATPase-2A (SERCA2A) structure is partially preserved in exercise pre-conditioned hearts (53, 54). The observation that the SERCA2A is protected against ischemic modification in exercised hearts may also suggest an interface between Ca2+ mechanisms and prevention of oxidative stress. Indeed, investigators demonstrated a strong association between antioxidant capacity, oxidative stress prevention, and preservation of SERCA2A damage in exercised hearts exposed to an ischemic insult (53, 54). Although the specific antioxidants that are responsible for these anti-infarct responses remain elusive, it is clear that an isoform of the endogenous antioxidant superoxide dismutase-2 (SOD2), found in the mitochondria, is rapidly overexpressed and allosterically activated following exercise pre-conditioning (61, 166). Moreover, since antioxidants suppress free radicals and other radical species through a network of chemical reactions, it is unlikely that SOD2 is preventing oxidative stress on its own. In support, a series of well-designed experiments demonstrated that the glutathione system is essential in protecting the exercise pre-conditioned heart in cooperation with SOD2, and perhaps other endogenous antioxidants found in ventricular myocytes (55, 56). It is also possible that antioxidant protection may be provided to the exercised heart through up-regulation of non-traditional antioxidants such as heat shock proteins. Indeed, numerous studies have now demonstrated that a family of heat shock proteins are overexpressed in the hearts of exercised animals, although their essentiality to the exercise pre-conditioning response remains unproven (35, 62, 126).
Upregulation of miR-128 Mediates Heart Injury by Activating Wnt/β-catenin Signaling Pathway in Heart Failure Mice
Published in Organogenesis, 2021
Jing-Yao Li, Xin-Chang Li, Yu-Long Tang
Cascades of signaling pathways and a portfolio of genes have been identified to serve as potential targets for therapeutic interventions in the heart disorders.4–7 For example, cytosolic calcium homeostasis mediated by sarcoendoplasmic reticulum calcium ATPase (SERCA2a) is a critical regulator in respect to cardiac contraction.8,9 Wnt signaling is a well-known evolutionarily conserved and developmental signaling pathway for its role in various respects including inflammation, organ development, tissue homeostasis, embryogenesis, and injury repair.10,11 Over the past decade, the critical role of Wnt signaling has been recognized in cardiac physiology and pathophysiology. A canonical Wnt signaling pathway dominantly mediated by a central signal transducer β-catenin has been characterized to play notable roles in activation of heart regenerative process and heart remodeling in response to cardiac injury.12–14 Aberrant Wnt/β-catenin activation leads to onset and progression of cardiac dysfunction such as cardiac hypertrophy, fibrosis, arrhythmias, and infarction.15,16 Wnt1, a signature element of the early Wnt/β-catenin signaling, is a specific and potent inducer of angiogenesis and fibrosis in heart repair following acute cardiac injury.17 However, investigation and detailed understanding of molecular strategy of Wnt1/β-catenin pathway in pathophysiological cardiac hypertrophy and heart failure remain largely elusive.
Five New Cases of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS), with One Case Showing a Novel Mutation
Published in Fetal and Pediatric Pathology, 2021
Alyssa Kalsbeek, Renee Dhar-Dass, Abdul Hanan, Eman Al-Haddad, Iman William, Adina Alazraki, Janet Poulik, Kasey McCollum, Aya Almashad, Bahig M. Shehata
Mechanisms involving abnormalities of calcium influx in the smooth muscle include the interstitial cells of Cajal that serve as pacemaker cells in the gastrointestinal tract for smooth muscle contraction and respond to neurotransmitters through calcium-activated chloride channels. Abnormal cellular concentrations of calcium can result from defects in the calcium regulating proteins and can impair muscle contractility [21]. Plasma membrane calcium ATPase or PMCA4 is localized in the smooth muscle layers of the intestinal wall and is likely involved in calcium signaling and peristalsis. ATP2B4 encodes PMCA4, which is tightly regulated by cells of Cajal and functions to regulate calcium flux across the plasma membrane [22]. In support of this hypothesis altered contractility of bladder wall smooth muscle was shown in PMCA4 deficient mice which is analogous to the megacystis seen in MMIHS [23].
Cadmium exposure induces cardiac glucometabolic dysregulation and lipid accumulation independent of pyruvate dehydrogenase activity
Published in Annals of Medicine, 2021
Olufemi I. Oluranti, Ebunoluwa A. Agboola, Nteimam E. Fubara, Mercy O. Ajayi, Olugbenga S. Michael
In diabetic cardiomyopathy (DCM), as shown by animal models, cardiac glycolysis and pyruvate oxidation are both affected. The mechanisms involved in reducing the oxidation of glucose in the DCM also include decreased expression and activity of essential enzymes of glucose oxidation, including G6P and PDH [52]. There is an accumulation of glycolytic intermediates as a result of decreased myocardial glycolysis and glucose oxidation in DCM. These glycolytic intermediates are linked to increased production of reactive oxygen species (ROS) [53], decreased expression of calcium ATPase 2a (SERCA2a) in the sarcoplasmic reticulum [54] and increased accumulation of Ca2+, all contributing to cardiac dysfunction. However, the increase in the activity of the pyruvate dehydrogenase (PDH) enzyme in the heart is unexplained in this report, which needs further investigation. Elevated levels of circulating free fatty acids in obesity and diabetes increase the availability of fatty acids in the heart, where increased oxidation of fatty acids will minimize glucose oxidation by impairing the activity of pyruvate dehydrogenase (PDH), leading to a decrease in energy efficiency [55].