Intercellular and extracellular adhesion signals control cardiac myocyte structural and functional remodeling: mechanosensing mediated by cadherin and hyaluronan receptors

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

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Raf-1 kinase activity is necessary and sufficient for gene expression changes but not sufficient for cellular morphology changes associated with cardiac myocyte hypertrophy.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)43853-7 ◽

1994 ◽

Vol 269 (48) ◽

pp. 30580-30586

Author(s):

J Thorburn ◽

M McMahon ◽

A Thorburn

Keyword(s):

Gene Expression ◽

Cardiac Myocyte ◽

Kinase Activity ◽

Cellular Morphology ◽

Myocyte Hypertrophy ◽

Cardiac Myocyte Hypertrophy ◽

Necessary And Sufficient ◽

Morphology Changes

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Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22084167 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4167

Author(s):

Xiaonan Sun ◽

Jalen Alford ◽

Hongyu Qiu

Keyword(s):

Regulatory Network ◽

Molecular Basis ◽

Therapeutic Potential ◽

Research Direction ◽

Future Research ◽

Cardiac Diseases ◽

Functional Remodeling ◽

Underlying Mechanisms ◽

Mitochondrial Remodeling ◽

Normal Cellular Function

Mitochondria undergo structural and functional remodeling to meet the cell demand in response to the intracellular and extracellular stimulations, playing an essential role in maintaining normal cellular function. Merging evidence demonstrated that dysregulation of mitochondrial remodeling is a fundamental driving force of complex human diseases, highlighting its crucial pathophysiological roles and therapeutic potential. In this review, we outlined the progress of the molecular basis of mitochondrial structural and functional remodeling and their regulatory network. In particular, we summarized the latest evidence of the fundamental association of impaired mitochondrial remodeling in developing diverse cardiac diseases and the underlying mechanisms. We also explored the therapeutic potential related to mitochondrial remodeling and future research direction. This updated information would improve our knowledge of mitochondrial biology and cardiac diseases’ pathogenesis, which would inspire new potential strategies for treating these diseases by targeting mitochondria remodeling.

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Statistical Approach to Incorporating Experimental Variability into a Mathematical Model of the Voltage-Gated Na+ Channel and Human Atrial Action Potential

Cells ◽

10.3390/cells10061516 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1516

Author(s):

Daniel Gratz ◽

Alexander J Winkle ◽

Seth H Weinberg ◽

Thomas J Hund

Keyword(s):

Action Potential ◽

Mathematical Models ◽

Cardiac Myocyte ◽

Population Level ◽

Na Channel ◽

Model Parameters ◽

Healthy Population ◽

Experimental Measurements ◽

Voltage Gated ◽

Experimental Variability

The voltage-gated Na+ channel Nav1.5 is critical for normal cardiac myocyte excitability. Mathematical models have been widely used to study Nav1.5 function and link to a range of cardiac arrhythmias. There is growing appreciation for the importance of incorporating physiological heterogeneity observed even in a healthy population into mathematical models of the cardiac action potential. Here, we apply methods from Bayesian statistics to capture the variability in experimental measurements on human atrial Nav1.5 across experimental protocols and labs. This variability was used to define a physiological distribution for model parameters in a novel model formulation of Nav1.5, which was then incorporated into an existing human atrial action potential model. Model validation was performed by comparing the simulated distribution of action potential upstroke velocity measurements to experimental measurements from several different sources. Going forward, we hope to apply this approach to other major atrial ion channels to create a comprehensive model of the human atrial AP. We anticipate that such a model will be useful for understanding excitability at the population level, including variable drug response and penetrance of variants linked to inherited cardiac arrhythmia syndromes.

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Excitation spread in cardiac myocyte cultures using paired microelectrode and microelectrode array recordings

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2007.03.007 ◽

2007 ◽

Vol 42 (6) ◽

pp. S3 ◽

Cited By ~ 5

Author(s):

P. Athias ◽

S. Jacquir ◽

C. Tissier ◽

D. Vandroux ◽

S. Binczak ◽

...

Keyword(s):

Microelectrode Array ◽

Cardiac Myocyte ◽

Array Recordings

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Smooth muscle myosin light chain kinase expression in cardiac and skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.5.c1656 ◽

2000 ◽

Vol 279 (5) ◽

pp. C1656-C1664 ◽

Cited By ~ 44

Author(s):

B. Paul Herring ◽

Shelley Dixon ◽

Patricia J. Gallagher

Keyword(s):

Skeletal Muscle ◽

Smooth Muscle ◽

Light Chain ◽

Myosin Light Chain Kinase ◽

Myosin Light Chain ◽

Cardiac Myocyte ◽

Cardiac Tissue ◽

Specific Protein ◽

Myoblast Differentiation ◽

Adult Skeletal Muscle

The purpose of this study was to characterize myosin light chain kinase (MLCK) expression in cardiac and skeletal muscle. The only classic MLCK detected in cardiac tissue, purified cardiac myocytes, and in a cardiac myocyte cell line (AT1) was identical to the 130-kDa smooth muscle MLCK (smMLCK). A complex pattern of MLCK expression was observed during differentiation of skeletal muscle in which the 220-kDa-long or “nonmuscle” form of MLCK is expressed in undifferentiated myoblasts. Subsequently, during myoblast differentiation, expression of the 220-kDa MLCK declines and expression of this form is replaced by the 130-kDa smMLCK and a skeletal muscle-specific isoform, skMLCK in adult skeletal muscle. These results demonstrate that the skMLCK is the only tissue-specific MLCK, being expressed in adult skeletal muscle but not in cardiac, smooth, or nonmuscle tissues. In contrast, the 130-kDa smMLCK is ubiquitous in all adult tissues, including skeletal and cardiac muscle, demonstrating that, although the 130-kDa smMLCK is expressed at highest levels in smooth muscle tissues, it is not a smooth muscle-specific protein.

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Human fetal cardiac myocyte growth is mediated by activation of class 1A/1B pi 3-kinase, Akt, PKC, and ERK signaling

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2007.03.753 ◽

2007 ◽

Vol 42 (6) ◽

pp. S84-S85

Author(s):

Lakshman Sandirasegarane ◽

Swarajit K. Biswas ◽

Yan Zhao ◽

Lawrence I. Sinoway

Keyword(s):

Cardiac Myocyte ◽

Erk Signaling

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