Victor Chang Cardiac Research Institute

About: Victor Chang Cardiac Research Institute is a nonprofit organization based out in Sydney, New South Wales, Australia. It is known for research contribution in the topics: Mechanosensitive channels & Heart failure. The organization has 708 authors who have published 1599 publications receiving 70035 citations.

The L‐type Ca2+ channel facilitates abnormal metabolic activity in the cTnI‐G203S mouse model of hypertrophic cardiomyopathy

Abstract: KEY POINTS Genetic mutations in cardiac troponin I (cTnI) are associated with development of hypertrophic cardiomyopathy characterized by myocyte remodelling, disorganization of cytoskeletal proteins and altered energy metabolism. The L-type Ca(2+) channel is the main route for calcium influx and is crucial to cardiac excitation and contraction. The channel also regulates mitochondrial function in the heart by a functional communication between the channel and mitochondria via the cytoskeletal network. We find that L-type Ca(2+) channel kinetics are altered in cTnI-G203S cardiac myocytes and that activation of the channel causes a significantly greater increase in mitochondrial membrane potential and metabolic activity in cTnI-G203S cardiac myocytes. These responses occur as a result of impaired communication between the L-type Ca(2+) channel and cytoskeletal protein F-actin, involving decreased movement of actin-myosin and block of the mitochondrial voltage-dependent anion channel, resulting in a 'hypermetabolic' mitochondrial state. We propose that L-type Ca(2+) channel antagonists, such as diltiazem, might be effective in reducing the cardiomyopathy by normalizing mitochondrial metabolic activity. ABSTRACT Genetic mutations in cardiac troponin I (cTnI) account for 5% of families with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is associated with disorganization of cytoskeletal proteins and altered energy metabolism. The L-type Ca(2+) channel (ICa-L ) plays an important role in regulating mitochondrial function. This involves a functional communication between the channel and mitochondria via the cytoskeletal network. We investigate the role of ICa-L in regulating mitochondrial function in 25- to 30-week-old cardiomyopathic mice expressing the human disease-causing mutation Gly203Ser in cTnI (cTnI-G203S). The inactivation rate of ICa-L is significantly faster in cTnI-G203S myocytes [cTnI-G203S: τ1 = 40.68 ± 3.22, n = 10 vs. wild-type (wt): τ1 = 59.05 ± 6.40, n = 6, P < 0.05]. Activation of ICa-L caused a greater increase in mitochondrial membrane potential (Ψm , 29.19 ± 1.85%, n = 15 vs. wt: 18.84 ± 2.01%, n = 10, P < 0.05) and metabolic activity (24.40 ± 6.46%, n = 8 vs. wt: 9.98 ± 1.57%, n = 9, P < 0.05). The responses occurred because of impaired communication between ICa-L and F-actin, involving lack of dynamic movement of actin-myosin and block of the mitochondrial voltage-dependent anion channel. Similar responses were observed in precardiomyopathic mice. ICa-L antagonists nisoldipine and diltiazem decreased Ψm to basal levels. We conclude that the Gly203Ser mutation leads to impaired functional communication between ICa-L and mitochondria, resulting in a 'hypermetabolic' state. This might contribute to development of cTnI-G203S cardiomyopathy because the response is present in young precardiomyopathic mice. ICa-L antagonists might be effective in reducing the cardiomyopathy by altering mitochondrial function.

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia.

Abstract: The generation, maturation and remodelling of the extracellular matrix (ECM) are essential for the formation of alveoli during lung development. Alveoli formation is disturbed in preterm infants that develop bronchopulmonary dysplasia (BPD), where collagen fibres are malformed, and perturbations to lung ECM structures may underlie BPD pathogenesis. Malformed ECM structures might result from abnormal protein cross-linking, in part attributable to the increased expression and activity of transglutaminase 2 (TGM2) that have been noted in affected patient lungs, as well as in hyperoxia-based BPD animal models. The objective of the present study was to assess whether TGM2 plays a causal role in normal and aberrant lung alveolarization. Targeted deletion of Tgm2 in C57BL/6J mice increased septal thickness and reduced gas-exchange surface area in otherwise normally developing lungs. During aberrant lung alveolarization that occurred under hyperoxic conditions, collagen structures in Tgm2-/- mice were partially protected from the impact of hyperoxia, where normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance was restored; however, the lung alveolar architecture remained abnormal. Inhibition of transglutaminases (including TGM2) with cysteamine appreciably reduced transglutaminase activity in vivo, as assessed by Ne -(γ-l-glutamyl)-l-lysine abundance and TGM catalytic activity, and restored normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance under pathological conditions. Furthermore, a moderate improvement in alveoli size and gas-exchange surface density was noted in cysteamine-treated mouse lungs in which BPD was modelled. These data indicate that TGM2 plays a role in normal lung alveolarization, and contributes to the formation of aberrant ECM structures during disordered lung alveolarization.

Dissecting Cardiac Hypertrophy and Signaling Pathways Evidence for an Interaction Between Multifunctional G Proteins and Prostanoids

Abstract: Over the past two decades, the ability to produce genetically engineered animal models has been widely used to unravel complex biological pathways involved in both physiology and disease. Although uniquely powerful and inherently elegant, these models, while often providing surprising new insights, have not uncommonly raised more questions than they have answered. A case in point is a transgenic mouse model developed to probe the in vivo role of the G protein, Gh, in cardiac signaling, and its consequences.1 Unlike “traditional” heterotrimeric G proteins, Gh is decidedly atypical, being a multifunctional protein with both GTPase and transglutaminase (TGase) activity, and showing no sequence identity with other GTP-binding proteins. Moreover, although similar mouse models developed to study the role of Gq (a heterotrimeric G protein that, like Gh, mediates α1-adrenergic receptor (α1-AR) signaling, as well as that by other Ca2+-mobilizing receptors) provided clear evidence for its critical involvement in pressure-overload hypertrophy via a mechanism involving protein kinase Ce (PKCe) and phospholipase C (PLC) activation,1,2 that for Gh demonstrated a mild form of hypertrophy by a mechanism that remained elusive. Evidence for PKCe and PLC activation was lacking, and it was suggested, largely by default, that the hypertrophy in the cardiac Gh animals was due not to its signaling activity but to TGase-mediated protein crosslinking. In this issue of Circulation Research , FitzGerald and coworkers3 have reexamined this issue using an independently developed model of cardiac-restricted Gh overexpression. Interestingly, these studies provide evidence linking two major biological systems, transglutaminases (TGs) and prostanoids, in the cardiac dysfunction and hypertrophy observed in this transgenic model, and potentially contributing to these disorders in humans. TGs are a family of Ca2+- and thiol-dependent enzymes that catalyze …

Epicardial Origin of Resident Mesenchymal Stem Cells in the Adult Mammalian Heart

Abstract: The discovery of stem and progenitor cells in the adult mammalian heart has added a vital dimension to the field of cardiac regeneration. Cardiac-resident stem cells are likely sequestered as reserve cells within myocardial niches during the course of embryonic cardiogenesis, although they may also be recruited from external sources, such as bone marrow. As we begin to understand the nature of cardiac-resident stem and progenitor cells using a variety of approaches, it is evident that they possess an identity embedded within their gene regulatory networks that favours cardiovascular lineage potential. In addition to contributing lineage descendants, cardiac stem cells may also be stress sensors, offering trophic cues to other cell types, including cardiomyocytes and vasculature cells, and likely other stem cells and immune cells, during adaptation and repair. This presents numerous possibilities for endogenous cardiac stem and progenitor cells to be used in cell therapies or as targets in heart rejuvenation. In this review, we focus on the epicardium as an endogenous source of multi-potential mesenchymal progenitor cells in development and as a latent source of such progenitors in the adult. We track the origin and plasticity of the epicardium in embryos and adults in both homeostasis and disease. In this context, we ask whether directed activation of epicardium-derived progenitor cells might have therapeutic application.

Wide Turn Diversity in Protein Transmembrane Helices Implications for G-Protein-Coupled Receptor and Other Polytopic Membrane Protein Structure and Function

Abstract: Previously, we showed that perturbations of protein transmembrane helices are manifested as one of three types of noncanonical structures (wide turns, tight turns, and kinks), which, compared with α-helices, are evident by distinctive Cα i →Cα x distances. In this study, we report the analysis of more than 3000 transmembrane helices in 244 crystal structures from which we identified 70 wide turns (29 proline- and 41 nonproline-induced). Based on differences in the Cα i →Cα i -4 and Cα i →Cα i -5 profiles, we show that wide turns can be subclassified into three distinct subclasses (W1, W2, and W3) that differ with regard to the number and position of backbone i → i -5 H-bonds formed N-terminal to the perturbing or signature proline or nonproline residue. Although wide turns generally produce changes in helical direction of 20° to 30° and a lateral shift in the helical axis, some of the W3 subclass are associated with changes of <5°. We also show that the distinct architectural features of wide turns allow the carbonyl bond of the i - 4th residue, which is located on the widened loop of a wide turn, to be directed away from the helical axis. This provides regions of flexibility within helical regions allowing, for example, unique opportunities for interhelical H-bonding, including interactions with glycine zipper motifs, and for ion and cofactor binding. Furthermore, differences in wide-turn subtype usage by related protein family members, such as the G-protein-coupled receptors rhodopsin and the β2-adrenergic receptor, can significantly affect the orientation and position of residues critical for ligand binding and receptor activation.