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Mechanotransduction Mechanisms for Intraventricular Diastolic Vortex Forces and Myocardial Deformations: Part 2

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Abstract

Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. A primary goal of translational cardiovascular research is recognizing whether disease-related changes in phenotype can be averted by eliminating or reducing the effects of environmental epigenetic risks. There may be significant medical benefits in using gene-by-environment interaction knowledge to prevent or reverse organ abnormalities and disease. This survey proposes that “environmental” forces associated with diastolic RV/LV rotatory flows exert important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations. Mechanisms analogous to Murray’s law of hydrodynamic shear-induced endothelial cell modulation of vascular geometry are likely to link diastolic vortex-associated shear, torque and “squeeze” forces to RV/LV adaptations. The time has come to explore a new paradigm in which such forces play a fundamental epigenetic role, and to work out how heart cells react to them. Findings from various imaging modalities, computational fluid dynamics, molecular cell biology and cytomechanics are considered. The following are examined, among others: structural dynamics of myocardial cells (endocardium, cardiomyocytes, and fibroblasts), cytoskeleton, nucleoskeleton, and extracellular matrix; mechanotransduction and signaling; and mechanical epigenetic influences on genetic expression. To help integrate and focus relevant pluridisciplinary research, rotatory RV/LV filling flow is placed within a working context that has a cytomechanics perspective. This new frontier in cardiac research should uncover versatile mechanistic insights linking filling vortex patterns and attendant forces to variable expressions of gene regulation in RV/LV myocardium. In due course, it should reveal intrinsic homeostatic arrangements that support ventricular myocardial function and adaptability.

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Sources of Funding

Research support, for work from my Laboratory surveyed here, was provided by: National Heart, Lung, and Blood Institute, Grant R01 NIH 50446; National Science Foundation, Grant CDR 8622201; and North Carolina Supercomputing Center and Cray Research.

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Authors and Affiliations

  1. Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA

    Ares Pasipoularides

  2. Duke/NSF Research Center for Emerging Cardiovascular Technologies, Durham, NC, USA

    Ares Pasipoularides

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  1. Ares Pasipoularides
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Correspondence to Ares Pasipoularides.

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Editor-in-Chief Jennifer L. Hall oversaw the review of this article

Glossary

Compression (compressional stress)

The stress that squeezes something; the opposite of tension. The “pushing” stress component that acts perpendicular to a surface; compression in one (axial) direction induces tension in the other two (lateral) directions.

Creep

The deformation (stretch) of a material under constant load over time; myocardial creep entails extracellular matrix (ECM) and cardiomyocyte elongation, myofiber slippage, and other histoarchitectonic changes.

Cytoskeleton (CSK)

The fibrous proteins within a cell that provide tensegrity type structural support to the cell and are involved in mechanotransduction. The cytoskeleton provides physical, high-speed, linkage between the cell membrane and putative intracellular stress-sensing components, including the nucleus, which respond to mechanical cues through multiple pathways.

Epigenetics

(Gk. for “above/on top of" genetics) Refers to external modifications to DNA and its associated histone proteins that turn genes "on" or "off," without altering the DNA base sequence.

Epigenome

The complete set of epigenetic modifications (e.g., DNA methylation, histone acetylation, and chromatin remodeling) on the genome and allied histone proteins of a cell, tissue or organ.

Extracellular matrix (ECM)

The dynamic macromolecular complex synthesized primarily by fibroblasts, which assembles into a network that surrounds cells. It not only provides essential physical scaffolding, but also initiates crucial biomechanical and biochemical cues required for tissue function and adaptations.

Focal adhesion kinase (FAK)

Cytoplasmic enzyme that plays a major role in integrin-mediated signaling cascades. The size of the signal cascade can increase rapidly, allowing for a large response, to small initiating mechanical cues, such as diastolic vortical shear and “squeeze” forces.

Gene expression

The phenomenon whereby a gene is transcribed into an RNA molecule.

Genome (human)

All the DNA—in humans, encompassing about 3 billion DNA base pairs—coiled and recoiled around aggregated proteins (histones) in 23 distinct (single or haploid set) chromosomes within the nucleus, allowing control of the accessibility of DNA information. Mitochondrial DNA, distinct from nuclear DNA, is a small genome contained in all mitochondria.

Genotype

The inherited genetic makeup of a cell.

Hippo pathway

Signaling pathway that plays a restraining role in the control of organ growth and size via a cascade of protein kinases, which phosphorylates TAZ and YAP, causing them to be retained in the cytoplasm; in the nucleus, TAZ and YAP act as transcriptional regulators. In the developing heart, Hippo is a negative regulator of the pro-growth Wnt signaling pathway.

Histoarchitectonics

(Gk. ιστός = "tissue" + αρχιτεκτονική = "architecture") The adjustable cellular and non-cellular composition, changing intricate form patterns, and dynamic geometric arrangements of organs and tissues; investigated using various modalities, recognizing that form, structure, and function are inseparable.

KASH

One of two protein families (KASH/SUN domains) that are jointly responsible for holding together the two nuclear envelope membranes, and for attaching them to the cytoskeleton and the nucleoskeleton. A branched F-actin cytoskeleton permeating the cytoplasm is linked to the nuclear envelope via the KASH/SUN integral membrane protein complexes and to the cell membrane via membrane-embedded integrin proteins.

LINC (Linker of Nucleoskeleton and Cytoskeleton)

Complexes built from members of two protein families, SUN and KASH. SUN domain proteins are integral to the inner nuclear membrane, whereas KASH domain proteins reside in the outer nuclear membrane. SUN and KASH proteins directly bind each other, thereby forming a bridge across the nuclear envelope, which is essential for enhanced CSK/NSK force-coupling and for physical and functional linkage between the cytoplasm and nucleoplasm.

Mechanotransduction

How mechanical forces/cues are sensed and transduced into biochemical signals affecting cellular, tissue, and organ function and morphomechanical adaptations; involved are stretch-activated channels (SAC), cell adhesion receptors, extracellular matrix, cytoskeletal, and nucleoskeletal molecules, etc.

Next Generation Sequencing (NGS)

High-throughput DNA and RNA (coding and non-coding) sequencing methods that massively parallelize the sequencing process, producing thousands or millions of sequences at once; they can explore gene expression changes, epigenomic pattern, etc., on a genome-wide scale and with single-base precision.

Nuclear envelope

A double lipid bilayer membrane with multiple pores that surrounds the nucleus. The pores regulate the passage of macromolecules like proteins and RNA; since information is carried by the macromolecules, the envelope exerts some control over its flow.

Nucleoskeleton (NSK)

The fibrillar substructure of the nuclear matrix, primarily composed of intermediate filaments that consist of lamin proteins; it supports signaling, chromatin remodeling, DNA replication, and mRNA synthesis, processing and transport.

Paralogs

(Gk. para: “in parallel”) Genes [proteins] related by duplication within a genome and passed on side-by-side.

Phenotype

The observable morphomechanical characteristics of a cell, tissue, organ, or organism, which are based on the genotype and environmental factors.

Phenotypic plasticity

The capacity of a cell, tissue, organ, or organism, to change its morphomechanical state in response to “environmental” stimuli.

Remodeling

The (mal)adaptive change of tissue and organ morphology due to external or internal stimuli.

Sarcolemma

(sarco-, Gk.: pertaining to flesh; + lemma, Gk.: sheath) myocyte cell membrane.

Shear stress

A stress state where the stress is acting parallel to a given surface, as opposed to a normal (compression or tension) stress where the stress is vertical to the surface. When viscous fluids (e.g., blood) flow along surfaces, they generate shear stresses "pulling" tangentially on them, causing angular distortions.

Strain

A description of deformation (extension, shortening, volume change, or angular distortion) in terms of relative displacement of particles in a body under stress, which excludes rigid-body motions.

Stress

The force per unit area acting upon an object or material tending to cause it to change shape or volume.

SUN

One of two protein families (KASH/SUN domains) that are jointly responsible for holding together the two nuclear envelope membranes and for attaching them to the cytoskeleton and the nucleoskeleton. A branched F-actin cytoskeleton permeating the cytoplasm is linked to the nuclear envelope via the KASH/SUN integral membrane protein complexes and to the cell membrane via membrane-embedded integrin proteins.

TAZ (WW domain containing transcription regulator 1, or WWTR1)

Transcriptional coactivator and downstream effector of the Hippo pathway. Similarly to its paralog YAP, phosphorylated TAZ is sequestered in the cytoplasm and degraded; when dephosphorylated, TAZ/YAP translocates to the nucleus and interacts with other transcription factors to drive transcription, inducing gene expression.

Tensegrity structures

Arrangements consisting of components in tension and compression in stable equilibrium. The application of forces to a tensegrity structure will deform it into a slightly different shape in a way that supports the applied forces. Buckminster Fuller coined the word “tensegrity” from the words “tension” and “integrity.”

Tension (tensile stress)

The stress state leading to elongation in the tensile direction, while the volume stays constant; accordingly, the two other directions must decrease in size; i.e., a tension in one (axial) direction induces a compression in the other two (lateral) directions, and conversely. Tension is the opposite of compression.

Torque

The tendency of a force to rotate an object about a pivot. A torque can be thought of as a twist to an object that tends to produce rotation; e.g., pushing or pulling the handle of a wrench coupled to a nut or bolt produces a torque (turning force).

Traction (tractive force)

The force generating tangential motion of a surface, through viscous shear or dry friction exerted on the surface.

Transdifferentiation

Conversion of one differentiated cell type into another. It is a kind of transformation called metaplasia (Gk. for “change in form”).

Vortex

This is the rotating motion of a multitude of fluid particles around a common center; the paths of the individual particles do not have to be circular, but may also be asymmetric. The RV/LV diastolic filling vortex is a toroidal vortex, a torus-shaped or ring-shaped vortex, where blood spins around an imaginary axis line that forms a closed loop.

YAP (Yes-associated protein)

Transcriptional co-activator and downstream effector of the Hippo pathway. Similarly to its paralog TAZ, when phosphorylated YAP is isolated in the cytoplasm and degraded; when dephosphorylated, YAP/TAZ translocates to the nucleus and interacts with various transcription factors to induce gene expression.

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Pasipoularides, A. Mechanotransduction Mechanisms for Intraventricular Diastolic Vortex Forces and Myocardial Deformations: Part 2. J. of Cardiovasc. Trans. Res. 8, 293–318 (2015). https://doi.org/10.1007/s12265-015-9630-8

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  • DOI: https://doi.org/10.1007/s12265-015-9630-8

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