Publications
346 results found
Yamaguchi Y, Allegrini B, Rapetti-Mauss R, et al., 2021, Hereditary Xerocytosis: Differential Behavior of PIEZO1 Mutations in the N-Terminal Extracellular Domain Between Red Blood Cells and HEK Cells, FRONTIERS IN PHYSIOLOGY, Vol: 12, ISSN: 1664-042X
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- Citations: 3
Emig R, Zgierski-Johnston CM, Timmermann V, et al., 2021, Passive myocardial mechanical properties: meaning, measurement, models., Biophys Rev, Vol: 13, Pages: 587-610, ISSN: 1867-2450
Passive mechanical tissue properties are major determinants of myocardial contraction and relaxation and, thus, shape cardiac function. Tightly regulated, dynamically adapting throughout life, and affecting a host of cellular functions, passive tissue mechanics also contribute to cardiac dysfunction. Development of treatments and early identification of diseases requires better spatio-temporal characterisation of tissue mechanical properties and their underlying mechanisms. With this understanding, key regulators may be identified, providing pathways with potential to control and limit pathological development. Methodologies and models used to assess and mimic tissue mechanical properties are diverse, and available data are in part mutually contradictory. In this review, we define important concepts useful for characterising passive mechanical tissue properties, and compare a variety of in vitro and in vivo techniques that allow one to assess tissue mechanics. We give definitions of key terms, and summarise insight into determinants of myocardial stiffness in situ. We then provide an overview of common experimental models utilised to assess the role of environmental stiffness and composition, and its effects on cardiac cell and tissue function. Finally, promising future directions are outlined.
Abu Nahia K, Migdal M, Quinn TA, et al., 2021, Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region, Cellular and Molecular Life Sciences, Vol: 78, Pages: 6669-6687, ISSN: 1420-682X
The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-β, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.
Jakob D, Klesen A, Allegrini B, et al., 2021, Piezol and BK<sub>ca</sub> channels in human atrial fibroblasts: Interplay and remodelling in atrial fibrillation, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 158, Pages: 49-62, ISSN: 0022-2828
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- Citations: 15
Ravens U, Kohl P, 2021, Mechanoelectric feedback in the human heart: A causal affair, HEART RHYTHM, Vol: 18, Pages: 1414-1415, ISSN: 1547-5271
Rog-Zielinska E, Kohl P, 2021, Nanoscopic t-tubular deformation during cardiac mechanical cycle, Publisher: SPRINGER, Pages: 45-45, ISSN: 0175-7571
Jakob D, Klesen A, Darkow E, et al., 2021, Heterogeneity and Remodeling of Ion Currents in Cultured Right Atrial Fibroblasts From Patients With Sinus Rhythm or Atrial Fibrillation, FRONTIERS IN PHYSIOLOGY, Vol: 12
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- Citations: 3
Darkow E, Nguyen TT, Stolina M, et al., 2021, Small Conductance Ca<SUP>2+</SUP>-Activated K<SUP>+</SUP> (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue, FRONTIERS IN PHYSIOLOGY, Vol: 12
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- Citations: 13
Rog-Zielinska EA, Moss R, Kaltenbacher W, et al., 2021, Nano-scale morphology of cardiomyocyte t-tubule/sarcoplasmic reticulum junctions revealed by ultra-rapid high-pressure freezing and electron tomography, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 153, Pages: 86-92, ISSN: 0022-2828
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- Citations: 11
Emig R, Knodt W, Krussig MJ, et al., 2021, Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing, CELLS, Vol: 10
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- Citations: 25
Wuelfers EM, Greiner J, Giese M, et al., 2021, Quantitative collagen assessment in right ventricular myectomies form patients with tetralogy of Fallot, EUROPACE, Vol: 23, Pages: I38-I47, ISSN: 1099-5129
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- Citations: 5
Rog-Zielinska EA, Scardigli M, Peyronnet R, et al., 2021, Beat-by-Beat Cardiomyocyte T-Tubule Deformation Drives Tubular Content Exchange, CIRCULATION RESEARCH, Vol: 128, Pages: 203-215, ISSN: 0009-7330
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- Citations: 14
Quinn TA, Kohl P, 2021, CARDIAC MECHANO-ELECTRIC COUPLING: ACUTE EFFECTS OF MECHANICAL STIMULATION ON HEART RATE AND RHYTHM, PHYSIOLOGICAL REVIEWS, Vol: 101, Pages: 37-92, ISSN: 0031-9333
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- Citations: 60
Haerdtner C, Kornemann J, Krebs K, et al., 2020, Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering, BASIC RESEARCH IN CARDIOLOGY, Vol: 115, ISSN: 0300-8428
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- Citations: 29
Al-Shammari H, Latif N, Sarathchandra P, et al., 2020, Expression and function of mechanosensitive ion channels in human valve interstitial cells., PLoS One, Vol: 15, Pages: e0240532-e0240532, ISSN: 1932-6203
BACKGROUND: The ability of heart valve cells to respond to their mechanical environment represents a key mechanism by which the integrity and function of valve cusps is maintained. A number of different mechanotransduction pathways have been implicated in the response of valve cells to mechanical stimulation. In this study, we explore the expression pattern of several mechanosensitive ion channels (MSC) and their potential to mediate mechanosensitive responses of human valve interstitial cells (VIC). METHODS: MSC presence and function were probed using the patch clamp technique. Protein abundance of key MSC was evaluated by Western blotting in isolated fibroblastic VIC (VICFB) and in VIC differentiated towards myofibroblastic (VICMB) or osteoblastic (VICOB) phenotypes. Expression was compared in non-calcified and calcified human aortic valves. MSC contributions to stretch-induced collagen gene expression and to VIC migration were assessed by pharmacological inhibition of specific channels. RESULTS: Two MSC types were recorded in VICFB: potassium selective and cation non-selective channels. In keeping with functional data, the presence of both TREK-1 and Kir6.1 (potassium selective), as well as TRPM4, TRPV4 and TRPC6 (cationic non-selective) channels was confirmed in VIC at the protein level. Differentiation of VICFB into VICMB or VICOB phenotypes was associated with a lower expression of TREK-1 and Kir6.1, and a higher expression of TRPV4 and TRPC6. Differences in MSC expression were also seen in non-calcified vs calcified aortic valves where TREK-1, TRPM4 and TRPV4 expression were higher in calcified compared to control tissues. Cyclic stretch-induced expression of COL I mRNA in cultured VICFB was blocked by RN-9893, a selective inhibitor of TRPV4 channels while having no effect on the stretch-induced expression of COL III. VICFB migration was blocked with the non-specific MSC blocker streptomycin and by GSK417651A an inhibitor of TRPC6/3. CONCLUSION: Aortic VIC ex
Zgierski-Johnston CM, Ayub S, Fernandez MC, et al., 2020, Cardiac pacing using transmural multi-LED probes in channelrhodopsin-expressing mouse hearts, PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, Vol: 154, Pages: 51-61, ISSN: 0079-6107
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- Citations: 18
MacDonald EA, Madl J, Greiner J, et al., 2020, Sinoatrial node structure, mechanics, electrophysiology and the chronotropic response to stretch in rabbit and mouse, Frontiers in Physiology, Vol: 11, Pages: 1-15, ISSN: 1664-042X
The rhythmic electrical activity of the heart’s natural pacemaker, the sinoatrial node (SAN), determines cardiac beating rate (BR). SAN electrical activity is tightly controlled by multiple factors, including tissue stretch, which may contribute to adaptation of BR to changes in venous return. In most animals, including human, there is a robust increase in BR when the SAN is stretched. However, the chronotropic response to sustained stretch differs in mouse SAN, where it causes variable responses, including decreased BR. The reasons for this species difference are unclear. They are thought to relate to dissimilarities in SAN electrophysiology (particularly action potential morphology) between mouse and other species and to how these interact with subcellular stretch-activated mechanisms. Furthermore, species-related differences in structural and mechanical properties of the SAN may influence the chronotropic response to SAN stretch. Here we assess (i) how the BR response to sustained stretch of rabbit and mouse isolated SAN relates to tissue stiffness, (ii) whether structural differences could account for observed differences in BR responsiveness to stretch, and (iii) whether pharmacological modification of mouse SAN electrophysiology alters stretch-induced chronotropy. We found disparities in the relationship between SAN stiffness and the magnitude of the chronotropic response to stretch between rabbit and mouse along with differences in SAN collagen structure, alignment, and changes with stretch. We further observed that pharmacological modification to prolong mouse SAN action potential plateau duration rectified the direction of BR changes during sustained stretch, resulting in a positive chronotropic response akin to that of other species. Overall, our results suggest that structural, mechanical, and background electrophysiological properties of the SAN influence the chronotropic response to stretch. Improved insight into the biophysical determinants of st
Darkow E, Rog-Zielinska EA, Madl J, et al., 2020, The lectin LecA sensitizes the human stretch-activated channel TREK-1 but not piezo1 and binds selectively to cardiac non-myocytes, Frontiers in Physiology, Vol: 11, Pages: 1-16, ISSN: 1664-042X
The healthy heart adapts continuously to a complex set of dynamically changing mechanical conditions. The mechanical environment is altered by, and contributes to, multiple cardiac diseases. Mechanical stimuli are detected and transduced by cellular mechano-sensors, including stretch-activated ion channels (SAC). The precise role of SAC in the heart is unclear, in part because there are few SAC-specific pharmacological modulators. That said, most SAC can be activated by inducers of membrane curvature. The lectin LecA is a virulence factor of Pseudomonas aeruginosa and essential for P. aeruginosa-induced membrane curvature, resulting in formation of endocytic structures and bacterial cell invasion. We investigate whether LecA modulates SAC activity. TREK-1 and Piezo1 have been selected, as they are widely expressed in the body, including cardiac tissue, and they are “canonical representatives” for the potassium selective and the cation non-selective SAC families, respectively. Live cell confocal microscopy and electron tomographic imaging were used to follow binding dynamics of LecA, and to track changes in cell morphology and membrane topology in human embryonic kidney (HEK) cells and in giant unilamellar vesicles (GUV). HEK cells were further transfected with human TREK-1 or Piezo1 constructs, and ion channel activity was recorded using the patch-clamp technique. Finally, freshly isolated cardiac cells were used for studies into cell type dependency of LecA binding. LecA (500 nM) binds within seconds to the surface of HEK cells, with highest concentration at cell-cell contact sites. Local membrane invaginations are detected in the presence of LecA, both in the plasma membrane of cells (by 17 min of LecA exposure) as well as in GUV. In HEK cells, LecA sensitizes TREK-1, but not Piezo1, to voltage and mechanical stimulation. In freshly isolated cardiac cells, LecA binds to non-myocytes, but not to ventricular or atrial cardiomyocytes. This cell type speci
Izu LT, Kohl P, Boyden PA, et al., 2020, Mechano-electric and mechano-chemo-transduction in cardiomyocytes, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 598, Pages: 1285-1305, ISSN: 0022-3751
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- Citations: 24
Bers DM, Kohl P, Chen-Izu Y, 2020, Mechanics and energetics in cardiac arrhythmias and heart failure, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 598, Pages: 1275-1277, ISSN: 0022-3751
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- Citations: 1
Kopton RA, Buchmann C, Moss R, et al., 2020, Electromechanical Assessment of Optogenetically Modulated Cardiomyocyte Activity, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
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- Citations: 1
Emig R, Zgierski-Johnston CM, Beyersdorf F, et al., 2020, Human atrial fibroblast adaptation to heterogeneities in substrate stiffness, Frontiers in Physiology, Vol: 10, Pages: 1-9, ISSN: 1664-042X
Fibrosis is associated with aging and many cardiac pathologies. It is characterized both by myofibroblast differentiation and by excessive accumulation of extracellular matrix proteins. Fibrosis-related tissue remodeling results in significant changes in tissue structure and function, including passive mechanical properties. This research area has gained significant momentum with the recent development of new tools and approaches to better characterize and understand the ability of cells to sense and respond to their biophysical environment. We use a novel hydrogel, termed CyPhyGel, to provide an advanced in vitro model of remodeling-related changes in tissue stiffness. Based on light-controlled dimerization of a Cyanobacterial Phytochrome, it enables contactless and reversible tuning of hydrogel mechanical properties with high spatial and temporal resolution. Human primary atrial fibroblasts were cultured on CyPhyGels. After 4 days of culturing on stiff (~4.6 kPa) or soft (~2.7 kPa) CyPhyGels, we analyzed fibroblast cell area and stiffness. Cells grown on the softer substrate were smaller and softer, compared to cells grown on the stiffer substrate. This difference was absent when both soft and stiff growth substrates were combined in a single CyPhyGel, with the resulting cell areas being similar to those on homogeneously stiff gels and cell stiffnesses being similar to those on homogeneously soft substrates. Using CyPhyGels to mimic tissue stiffness heterogeneities in vitro, our results confirm the ability of cardiac fibroblasts to adapt to their mechanical environment, and suggest the presence of a paracrine mechanism that tunes fibroblast structural and functional properties associated with mechanically induced phenotype conversion toward myofibroblasts. In the context of regionally increased tissue stiffness, such as upon scarring or in diffuse fibrosis, such a mechanism could help to prevent abrupt changes in cell properties at the border zone between normal a
Weber T, Zgierski-Johnston CM, Klein E, et al., 2020, CONCENTRIC, MEMS-BASED OPTOELECTROMECHANICAL PACER FOR MULTIMODAL CARDIAC EXCITATION, 33rd IEEE International Conference on Micro Electro Mechanical Systems (MEMS), Publisher: IEEE, Pages: 361-364, ISSN: 1084-6999
Noble D, Blundell T, Kohl P, 2019, PBMB Commentary on Editorial by Keith Baverstock Comment, PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, Vol: 149, Pages: 3-3, ISSN: 0079-6107
Brandenburg S, Pawlowitz J, Eikenbusch B, et al., 2019, Impact of regulated junctophilin-2 clustering at axial tubule junctions on atrial excitation-contraction coupling and therapeutic implications, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 686-686, ISSN: 0195-668X
Ahmed I, Merz J, Dimanski D, et al., 2019, Purinergic receptor Y6 (P2Y6) deficiency impairs left ventricular function, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 3948-3948, ISSN: 0195-668X
Karoutas A, Szymanski W, Rausch T, et al., 2019, The NSL complex maintains nuclear architecture stability via lamin A/C acetylation, NATURE CELL BIOLOGY, Vol: 21, Pages: 1248-+, ISSN: 1465-7392
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- Citations: 50
Verheyen J, Kohl P, Peyronnet R, 2019, The Institute for Experimental Cardiovascular Medicine in Freiburg., Biophys Rev, Vol: 11, Pages: 675-677, ISSN: 1867-2450
Chen J, Arentz T, Cochet H, et al., 2019, Extent and spatial distribution of left atrial arrhythmogenic sites, late gadolinium enhancement at magnetic resonance imaging, and low-voltage areas in patients with persistent atrial fibrillation: comparison of imaging vs. electrical parameters of fibrosis and arrhythmogenesis, EUROPACE, Vol: 21, Pages: 1484-1493, ISSN: 1099-5129
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- Citations: 46
Krebs K, Schmidt BL, Dufner B, et al., 2019, Adventitial macrophages invade the atherosclerotic plaque, 2nd Joint Meeting of the German-Society-for-Immunology (DGfl) and the Italian-Society-of-Immunology-Clinical-Immunology-and-Allergology (SIICA), Publisher: WILEY, Pages: 239-240, ISSN: 0014-2980
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