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Pathophysiology of Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Jacob Cao, John O'Sullivan, Sean Lal
As described previously, the sustained hyperadrenergic state that characterizes HF results in desensitization of cardiomyocytes to further adrenergic stimulation. As a result, there is increased phospholamban-dependent inhibition of SERCA-2a. Indeed, both phospholamban ablation and β blockade have been shown to improve excitation-contraction coupling and calcium handling in both animal and human studies. Upregulation of SERCA-2a function and expression have been trialed with varying success. Istaroxime, a direct SERCA-2a stimulator, has been shown to increase sarcoplasmic reticulum calcium reuptake during diastole and release during systole. In a randomized placebo-controlled trial of 120 patients with acute decompensated HF, istaroxime infusion was shown to improve left heart hemodynamics without any increase in adverse events.12 There are currently no studies examining istaroxime in chronic HFrEF. Post-translational protein modification has recently emerged as another area of research into improving SERCA-2a function. The conjugation of small ubiquitin-like modifiers (SUMO) to SERCA-2a has been shown to be essential in preserving SERCA-2a ATPase activity, and that HF is associated with a reduction in the extent of conjugation. Additionally, animal studies have demonstrated that restoration of SUMO1 via gene therapy improves cardiac function, with evidence in humans still pending.
Striated MusclesSkeletal and Cardiac Muscles
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
As a result of conformational change in the dihydropyridine receptor, the ryanodine receptor opens and releases Ca++ from the sarcoplasmic reticulum to the sarcoplasm: The free Ca++ concentration in the cells increases from 0.1 μM when resting to 10 μM during activity.Calcium binds to troponin-C, tropomyosin rolls deeper into the groove between the two actin strands exposing them to myosin, cross-bridges form, the inhibition of actomyosin ATPase by troponin-I is removed and contraction proceeds. The muscle relaxes when the sarcoplasmic reticulum sequesters calcium and the troponin-tropomyosin-mediated inhibition returns.Relaxation occurs when Ca++ in the sarcoplasm returns to the sarcoplasmic reticulum (SR) by SR Ca++ ATPase (sarcoplasmic/endoplasmic reticulum Ca++-ATPase [SERCA]) pump. The SERCA pump transports two calcium ions in exchange for the hydrolysis of one ATP molecule, functioning against the calcium gradient to restore endoplasmic luminal calcium levels. Intracellular Ca++ decreases and Ca++ is released from troponin-C, and tropomyosin blocks the myosin-binding site on actin.
Local Anesthetics
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Elena González Burgos, Luis Luis García-García, M. Pilar Gómez-Serranillos, Francisca Gómez Oliver
The LA injection causes toxicity resulting in trauma because of: (1) the injected volume; (2) the pressure of injection, and (3) chemically by varying intracellular concentrations of calcium (Nair, 2017). Regarding the later, increased free cytosolic Ca2+ concentration seems to be the primary cause. The mechanism of myotoxicity caused by LAs remains uncertain but it seems that multiple mechanisms are involved. Thus, LAs can bind and activate the ryanodine receptors (RyR) located in the sarcoplasmic reticulum membrane releasing more calcium from the SR to the cytosol and therefore leading to muscle contraction. Nevertheless, activation of the RyRs by LAs is both concentration- and pH-dependent. In fact, the charged form of the LA is the one able to activate the RyR. Inhibition of the ATPase responsible of the calcium reuptake into the SR (SERCA) by LAs also seems to contribute the disturbance of the calcium cellular homeostasis (Dippenaar, 2007). Two of the LAs with myotoxic properties are bupivacaine and ropivacaine, being the former more myotoxic than the latter. The probable reason for this difference in myotoxicity seems to be the higher liposolubility of bupivacaine compared with ropivacaine.
Cellular Calcium Signals in Cancer Chemoprevention and Chemotherapy by Phytochemicals
Published in Nutrition and Cancer, 2022
Xue Li, Shuhan Miao, Feng Li, Fen Ye, Guang Yue, Rongzhu Lu, Haijun Shen, Yang Ye
Curcumin is a natural phenolic compound obtained from Curcuma longa (106) with multiple activities including anti-proliferation, antioxidant, anti-inflammatory, antiviral and anticancer activities (107, 108). Curcumin causes cell death in different cancers through inducing apoptosis, cell cycle arrest, migration and autophagy (109, 110). Curcumin exerts anticancer effects by regulating calcium signaling in human papillary thyroid carcinoma cancer (111), ovarian cancer (61) and non-small cell lung cancer (112). Seo et al. reported that curcumin increases cytoplasmic Ca2+ concentration to induce apoptosis in ovarian cancer cells. SERCA is an important calcium pump that removes cytosolic Ca2+ to ER calcium stores, which is critical for calcium homeostasis. Curcumin increases cytoplasmic Ca2+ concentration through inhibiting the activity of SERCA with no effects on the expression of SERCA (61). These results indicated that curcumin inhibited SERCA activity to affect calcium homeostasis to prevent tumor growth. In addition, curcumin disrupts calcium homeostasis in human papillary thyroid carcinoma cells via inhibition of SERCA. The increased cytosolic Ca2+ concentration followed by activated calcium/calmodulin-dependent protein kinase II (CaMKII)-JNK signaling pathway and ER stress lead to apoptosis (111). In human non-small cell lung cancer, curcumin caused Ca2+ overload by Bcl-2-mediated IP3R phosphorylation, followed by the activation of cleaved caspase-3 and cleaved caspase-9 and the decrease of MMP and apoptosis (112).
Cardiotonic steroids as potential Na+/K+-ATPase inhibitors – a computational study
Published in Journal of Receptors and Signal Transduction, 2019
Chirag N. Patel, Sivakumar Prasanth Kumar, Krunal M. Modi, Mehul N. Soni, Nainesh R. Modi, Himanshu A. Pandya
Na+/K+-ATPase, is a membrane protein, associated in the formation of Na+ and K+ gradients across plasma membranes and in the persistence of cytoplasmic Na+ levels [1]. Three Na+ ions and two K+ ions were pumped by concentrated gradient which has been developed by Na+ pump through inside as well as outside the cell, applying this method the energy achieved by the hydrolysis of a molecule of ATP. Na+/K+-ATPase, urges various aspects of Na+/H+ and Na+/Ca2+ exchangers improving, cell volume, pH and Ca2+ levels [2–4]. Furthermore, signal transduction and cytoskeleton regulation was performed by Na+/K+-ATPase proteins which supervise the osmotic level of cell [5]. It also contributes to the catalytic cycle with specific peculiarities which is ephemeral phosphorylated form which is composition of ATP hydrolysis [1,6]. The cardiac pledges determined by Na+/K+-ATPase by transferring of Na+/Ca2+ exchanger which regulates the combination of intracellular Na+ to resolve the Ca2+ absorption over the Na+/Ca2+ exchange (Figure 1). In addition, sarcoplasmic reticulum (SR) acquires the Ca2+ from SR Ca2+ ATPase (SERCA) which remitted during consecutive exhilaration [7].
Biological therapies targeting arrhythmias: are cells and genes the answer?
Published in Expert Opinion on Biological Therapy, 2018
Debbie Falconer, Nikolaos Papageorgiou, Emmanuel Androulakis, Yasmin Alfallouji, Wei Yao Lim, Rui Providencia, Dimitris Tousoulis
Sarcoplasmic reticulum Ca-ATPase (SERCA) 2a is an ATPase pump that regulates cytosolic calcium concentration by transferring Ca into the lumen of the sarcoplasmic reticulum. Following ischemia, SERCA activity decreases, increasing cytosolic Ca and triggering afterdepolarizations [7]. SERCA2a was overexpressed in the left ventricles of pigs which had undergone LAD occlusion and reperfusion (Table 2). There was a significant reduction in arrhythmias of transfected animals compared with controls. There was no difference, however, in animals which had undergone artery occlusion but no reperfusion [77]. Deficient SERCA2a is also associated with cardiac failure. When transferred into the failing hearts of rats [78] and guinea pigs [79], ventricular arrhythmias were significantly suppressed. SERCA2a overexpression in the heart of healthy young guinea pigs resulted in a fourfold reduction in alternans-mediated ventricular arrhythmias [80].