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.

Exercise physiology in chronic mechanical circulatory support patients: vascular function and beyond.

Abstract: PURPOSE OF REVIEW The majority of patients currently implanted with left ventricular assist devices have the expectation of support for more than 2 years. As a result, survival alone is no longer a sufficient distinctive for this technology, and there have been many studies within the last few years examining functional capacity and exercise outcomes. RECENT FINDINGS Despite strong evidence for functional class improvements and increases in simple measures of walking distance, there remains incomplete normalization of exercise capacity, even in the presence of markedly improved resting hemodynamics. Reasons for this remain unclear. Despite current pumps being run at a fixed speed, it is widely recognized that pump outputs significantly increase with exercise. The mechanism of this increase involves the interaction between preload, afterload, and the intrinsic pump function curves. The role of the residual heart function is also important in determining total cardiac output, as well as whether the aortic valve opens with exercise. Interactions with the vasculature, with skeletal muscle blood flow and the state of the autonomic nervous system are also likely to be important contributors to exercise performance. SUMMARY Further studies examining optimization of pump function with active pump speed modulation and options for optimization of the overall patient condition are likely to be needed to allow left ventricular assist devices to be used with the hope of full functional physiological recovery.

Disruption of membrane cholesterol organization impairs the concerted activity of PIEZO1 channel clusters

Abstract: The human mechanosensitive ion channel PIEZO1 is gated by membrane tension and regulates essential biological processes such as vascular development and erythrocyte volume homeostasis. Currently, little is known about PIEZO1 plasma membrane localization and organization. Using a PIEZO1-GFP fusion protein, we investigated whether cholesterol enrichment or depletion by methyl-β-Cyclodextrin (MBCD) and disruption of membrane cholesterol organization by dynasore affects PIEZO1-GFP’s response to mechanical force. Electrophysiological recordings in the cell-attached configuration revealed that MBCD caused a rightward shift in the PIEZO1-GFP pressure-response curve, increased channel latency in response to mechanical stimuli and markedly slowed channel inactivation. The same effects were seen in native PIEZO1 in N2A cells. STORM super-resolution imaging revealed that, at the nano-scale, PIEZO1-GFP channels in the membrane associate as clusters sensitive to membrane manipulation. Both cluster distribution and diffusion rates were affected by treatment with MBCD (5 mM). Supplementation of poly-unsaturated fatty acids appeared to sensitize the PIEZO1-GFP response to applied pressure. Together, our results indicate that PIEZO1 function is directly dependent on the membrane mechanical properties and lateral organization of membrane cholesterol domains which coordinates the concerted activity of PIEZO1 channels. SUMMARY The essential mammalian mechanosensitive channel PIEZO1 organizes in the plasma membrane into nanometric clusters which depend on the integrity of cholesterol domains to rapidly detect applied force and especially inactivate syncronously, the most commonly altered feature of PIEZO1 in pathology.

High torsional energy disulfides: relationship between cross-strand disulfides and right-handed staples.

Abstract: Redox-active disulfides are capable of being oxidized and reduced under physiological conditions. The enzymatic role of redox-active disulfides in thiol-disulfide reductases is well-known, but redox-active disulfides are also present in non-enzymatic protein structures where they may act as switches of protein function. Here, we examine disulfides linking adjacent β-strands (cross-strand disulfides), which have been reported to be redox-active. Our previous work has established that these cross-strand disulfides have high torsional energies, a quantity likely to be related to the ease with which the disulfide is reduced. We examine the relationship between conformations of disulfides and their location in protein secondary structures. By identifying the overlap between cross-strand disulfides and various conformations, we wish to address whether the high torsional energy of a cross-strand disulfide is sufficient to confer redox activity or whether other factors, such as the presence of the cross-strand disulfide in a strained β-sheet, are required.