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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
Relaxation occurs when calcium concentration is lowered by the actions of Ca-ATPase on the longitudinal part of the sarcoplasmic reticulum. A protein called phospholamban normally inhibits sarcoplasmic reticulum Ca-ATPase, but when it is phosphorylated, it exerts less inhibition, so calcium uptake is enhanced. Calsequestrin present in the cytosol of cardiac muscle cells serves as a sink for calcium. In addition to the Ca-ATPase in the sarcolemma, the Na+/Ca++ exchanger pumps calcium out of the cell. The Na+/Ca++ exchanger operates on the basis of sodium ion gradient. Three sodium ions enter for every one calcium ion leaving the cell via the exchanger.
Arrhythmogenic Right Ventricular Cardiomyopathy
Published in Andrea Natale, Oussama M. Wazni, Kalyanam Shivkumar, Francis E. Marchlinski, Handbook of Cardiac Electrophysiology, 2020
Daniele Muser, Pasquale Santangeli
ARVC is a genetically determined cardiomyopathy with heterogeneous inheritance and clinical phenotype with variable penetrance and clinical severity of the disease among family trees. In up to 50% of the cases, a definite causal gene mutation cannot be found while desmosomal gene mutations are responsible for the disease in the 70% of cases with a positive genetic test.9 The first mutations causing the disease were found in 2000 in genes encoding for the desmosomal proteins plakoglobin and desmoplakin among patients with autosomal recessive Naxos and Carvajal cardiocutaneous syndromes, respectively.10–12 Both present woolly hair, keratoderma and arrhythmogenic cardiomyopathy with a higher incidence of LV involvement in the second one. Other desmosomal genes encoding for plakophilin, desmoglein, and desmocollin have also been discovered and have been associated to both autosomal recessive and dominant forms.13–15 In a lower proportion of cases, genes encoding for other non-desmosomal proteins like the ryanodine receptor and the transforming growth factor-β3 have been found.16,17 Mutations in the genes encoding for titin, lamin A/C and phospholamban have also been described and typically lead to arrhythmogenic syndromes characterized by a dilated cardiomyopathy phenotype overlapping with the classical ARVC phenotype.18–20
Molecular Biology of Calcium Pumps in Myometrium
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Joanne O’Reilly, Ashok Kumar Grover
One of the key differences between the SR and the PM Ca2+ pumps is their regulation during the excitation-contraction cycle. The PM Ca2+ pumps are activated by calmodulin and the cardiac SR pump is inhibited by phospholamban.5,15,17,41–43,59,60,62,64 The activation with calmodulin requires the presence of Ca2+, and similarly Ca2+ or phosphorylation of phospholamban by cAMP-dependent protein kinase dissociates this inhibitor from the Ca2+ pump. Thus both pumps have additional mechanisms for increased activity at the peak phase of contraction. The amount of calmodulin present in various tissues may vary. The phospholamban content of different tissues is even more variable.14 For instance, the SR Ca2+ pump from fast twitch muscle can be inhibited in vitro by phospholamban even though the tissue does not express this regulatory protein.42 Because the abundance of phospholamban present in various tissues does not correlate with the abundance of the pump protein, this regulation adds a dimension to tissue differentiation. In addition, in some studies the PM Ca2+ pump has been reported to be activated also by phosphorylation by cyclic nucleotide dependent protein kinase.41,64
Gene therapy to terminate tachyarrhythmias
Published in Expert Review of Cardiovascular Therapy, 2022
Kohei Kawajiri, Kensuke Ihara, Tetsuo Sasano
In the cardiac field, one of the diseases that has been studied earlier for treatment using CRISPR/Cas9 is Duchenne muscular dystrophy. Refaey et al. reported genome editing for dystrophic cardiac muscles in mice genetically engineered to develop Duchenne muscular dystrophy [112]. In this study, efficient truncation of mutant exon 23 of the Dmd gene restored dystrophin protein expression, cardiac fiber structure, and contraction of the papillary muscles. In the field of arrhythmia, as mentioned in the chapter on CPVT, genome editing by CRISPR/Cas9 has also been applied to knock-in mice with RyR2 mutant [100]. A study by Xie et al utilized CRISPR/Cas9 gene editing in mouse models of PRKAG2 cardiac syndrome, which is a hereditary disease caused by a mutation in the PRKAG2 gene and characterized by ventricular arrhythmia and progressive heart failure. The study demonstrated the therapeutic potential of CRISPR/Cas9 packaged into an AAV9 vector, which disabled the dominant mutant allele of the PRKAG2 gene [113]. In vivo editing for PRKAG2 transgenic and knock-in mice, left ventricular wall thickness was significantly reduced and ECG abnormalities were normalized. Dave et al. reported that genome editing reverses arrhythmia susceptibility in mice expressing the mutation in the phospholamban (PLN) gene associated with malignant arrhythmia and ventricular dilation [114]. This study showed that disruption of human PLN-deletion of Arg14 (R14del) allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice.
Efficacy and safety of saxagliptin for the treatment of type 2 diabetes mellitus
Published in Expert Opinion on Pharmacotherapy, 2020
If saxagliptin was actually assumed to be associated with an increased risk of heart failure, some possible underlying mechanisms could be proposed. A few authors have suggested that it could be secondary to elevated end-diastolic volumes and worsened endothelial dysfunction [92]. Koyani et al. reported that saxagliptin impaired the cardiac contractility via inhibiting the Ca2+/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca2+-ATPase 2a axis and the Na+-Ca2+ exchanger function in Ca2+ extrusion, resulting in a reduced Ca2+ content of the sarcoplasmic reticulum, diastolic Ca2+ overload, systolic dysfunction, and impaired cardiac contractile force [93]. In addition, they also recently reported the interaction of saxagliptin, but not of sitagliptin, with DPP-9, which could explain the former’s link with the onset of heart failure [94]. These studies provide clues for further investigation on the contribution of saxagliptin to the risk of heart failure.
Potential targets of gene therapy in the treatment of heart failure
Published in Expert Opinion on Therapeutic Targets, 2018
Jakub Rosik, Bartosz Szostak, Filip Machaj, Andrzej Pawlik
The therapeutic concept of gene therapy targeting was checked in small and large HF animal models. Pleger et al. administrated S100A1 in combination with an AAV6 vector to rats 10 weeks after a myocardial infarction. The results showed the largest improvement in the AAV6-S100A1-treated group when expressed as the percentage improvement in the ejection fraction. S100A1 also increased the cardiac contractility and the levels of calcium cycling proteins [i.e. SERCA2a and phospholamban (PLN)]. The addition of metoprolol to the therapy also reduced cardiac hypertrophy. Long-term, overexpressing S100A1, with or without additional beta-blockers, has beneficial effects on cardiomyocyte contractility and calcium circulation [32]. Similar results were also achieved in animal models; for example, AAV6-S100A1 and AAV9-S100A1 therapy resulted in improved diastolic and systolic heart function, a declining tendency of heart remodeling and improved energetic homeostasis [31,34].