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Kamkin A, Kiseleva I, editors. Mechanosensitivity in Cells and Tissues. Moscow: Academia; 2005.

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Mechanosensitivity in Cells and Tissues.

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Mechanically Mediated Crosstalk in Heart

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This review covers aspects of the cardiac mechanotransduction field at different levels, and advocates the possibility that mechanoelectro-chemical transduction forms part of a network of mechanically linked crosstalk in heart – Mechanically Mediated Crosstalk (MMC). It assembles evidence and observations in the literature to promote this hypothesis. Mechanical components can provide the bond between interactions at molecular, cellular, and macro levels to enable the crosstalk. Stretch activated channels exist in heart, but stresses and strains can affect other membrane channels or receptors. A cellular mechanical change can thus promote several ionic or downstream changes. Cell signal cascades have been implicated and, mostly via intracellular Ca, can affect membrane electrophysiology. MMC could shape downstream signals to alter intracellular Ca. MMC also spans other regulatory systems and processes, such as the autonomic nervous system, and in addition, operates through to the whole heart as an integrative system. Finally, supporting the hypothesis, if elements of the normal crosstalk become deranged it contributes to cardiovascular disease and, potentially, lethal arrhythmia.

Introduction

This review advocates the possibility that mechanoelectro-chemical transduction forms part of a network of what this article will term Mechanically Mediated Crosstalk (MMC) in heart. In support of this hypothesis it addresses disparate inputs in the cardiac mechanotransduction field at different levels. Some licence is taken in characterizing "crosstalk" as being a mechanical component, which provides a common link between the various interactions at molecular, cellular, and macro levels. In searching the literature to sustain the hypothesis, we track crosstalk along a path from mechanosensor to the whole heart within an integrative system. It spans other regulatory systems and processes. Finally, if elements of the normal crosstalk experience derangement, and the hypothesis holds, it contributes to cardiovascular disease, and potentially lethal arrhythmia.

Virtually all the anatomical subdivisions of the heart, membrane through to intact heart including man, show mechanoelectric transduction/coupling/ feedback, and although the exploration of the crosstalk begins from the bottom up, it uses a clock directional reference system, particularly in fig. 2.

Figure 2. Conjectural diagram of Mechanically Mediated Crosstalk (MMC) at cellular level.

Figure 2

Conjectural diagram of Mechanically Mediated Crosstalk (MMC) at cellular level. "Stress strain" represents intra and extracellular mechanical input - through extracellular matrix as well, e.g. physiological and biophysical force and pressure changes, (more...)

Mechanically mediated crosstalk (MMC) at the channel level

Passive, mechanically activated channels (Fig. 1 at 10 and 2 o'clock)

Stretch-activated channels (SAC) (Fig. 2 at 12 o'clock)

The regulatory integrative chain discussed in this article begins at the membrane with mechanogated, mechanosensitive channels. Since their definitive description, [38] stretch activated channels have been described in many tissues (for reviews see [15, 35, 75, 95] including heart [20]. Membrane stretch opens the channels to admit charge-carrying ions, which influences the membrane potential. Although the myocardium is actively contracting here, in the current context the resultant geometric shape changes are regarded as being passively transmitted.

Micropipette patch studies start with a residual membrane tension that may not be commensurate with that found in multicellular preparations, and multicellular preparations experience more tension than isolated cells (See also [7]). This questions the physiological validity of patch studies in the intact heart. However, characteristics of the channel electrophysiology have found equivalence in intact heart, where monophasic action potentials (MAPs) can be used to gain qualitative insights into cellular electrophysiology: for example isolated perfused heart of frog [61], and mammals [27, 34, 42]. Notably, there is a type of reversal potential, [61, 120] where a stretch early in the action potential produces a repolarising tendency, whereas if late it produces depolarisation. There is no change at the "reversal potential". There are other examples of the equivalence, in different guises, in intact heart in situ in experimental preparations [23] and in man [106]. SACs can thus explain load induced reductions in action potential duration in these examples. Another example is that SAC blockers in intact preparations are commonly used to block stretch induced electrophysiological changes. However, the results may have to be carefully interpreted. Streptomycin's effects as a blocker appear heterogeneous in intact atrium [4]. It looks so far as if SACs may well operate in intact heart.

Mechanically mediated crosstalk (MMC) and other channels

The hypothesis requires that the crosstalk applies to other channels apart from SACs. The ATP activated potassium (KATP) channel subunits (Kir6.1, Kir6.2, SUR1A, SUR1B, SUR2A, and SUR2B) [5] have been found in atria from neonatal rats. The KATP channel (Fig. 2 at 9 o'clock) is attached to the cytoskeleton, and it has been suggested to be mechanosensitive [111].

Several other channels appear to be mechanosensitive, including the L type Ca2+-channel [73] sodium channels [105] and the tandem pore potassium channels such as TREK-1 (Fig. 1 at 2 o'clock; Fig. 2 at 8 o'clock) [71], which appears not to involve the cytoskeleton - and IKAA [55], ion exchangers, (Fig. 2 at 1 o'clock) [84].

Figure 1. Broad interactions involving Mechanically Mediated Crosstalk (MMC).

Figure 1

Broad interactions involving Mechanically Mediated Crosstalk (MMC). Crosstalk is Mediated between membrane channels 1 & 2 (e.g. (Northwest and Northeast) stretch activated channels (SAC), and ATP activated potassium (KATP) channel), as well as (more...)

MMC and metabolism

In cultured chick ventricular myocytes, a stretch-activated ion channel [51] was identified as a high-conductance K+-selective channel blocked by gadolinium, tetraethylammonium, and charybdotoxin from the extracellular surface. It was identified as a Ca2+-activated K+ (KCa) channel type, also reversibly activated by ATP on the intracellular surface. That is, a stretch activated KCa,ATP channel.

The large (111 ± 3.0 pS) K+ channels, TREK-1: from the tandem pore family (Fig. 1 at 2 o'clock: Fig. 2 at 8 o'clock) which have been found in adult rat ventricular myocytes, are not only mechanosensitive, they are also activated by low intracellular pH, as well as intracellular ATP [107]. It does seem that there is a crosstalk with metabolism, albeit vestigial.

MMC and the neuro-humoral system

The autonomic nervous system, and the endocrine system are integrative regulatory systems, and they interact with each other. If the current hypothesis holds as a fully integrated system, the question arises as to whether MMC interplays with these other regulatory systems.

β Receptor (Fig. 2 at 11 o'clock)

Mechanically induced electrophysiological changes can be significantly modulated by β receptor agonism. This includes, first, the electrical restitution curve [45]. Load changes accentuate the supernormal period, and steepen the initial rising phase. β receptor agonism exacerbates these changes. Second, β receptor antagonism curtails mechanically induced arrhythmia [65]. Raised intraventricular pressure releases catecholamines from the ventricle [60] and this could promote mechanically induced arrhythmia. The β receptor effects would be via the cell signal chain involving β agonist/receptor, ATP, cAMP, and Ca channels. In support of this signal chain, catecholamine store depletion curtails mechanoarrhythmia whether the depletion is pharmacological [28] or by chronic sympathetic denervation in the intact preparation [29]. This notion has been further supported by a study in the intact preparation in which reserpine (also depletes catecholamines) and propranolol curtailed load-induced changes in electrical excitability and monophasic action potential duration [68].

Acetyl choline receptor (Fig. 2 at 11 o' clock)

G-protein regulated inward-rectifier potassium channels (GIRK) are part of a superfamily of inward-rectifier K+ channels. GIRK1 and 4 are found in atrium and sinoatrial node [72]. G-proteins and mechanical stretch (Fig 2 at 11 o' clock) modulates GIRK1-4 (also designated Kir3.1–4). Rabbit atrial muscarinic potassium channels are rapidly and reversibly inhibited by membrane stretch, possibly serving as part of the mechanoelectrical feedback interaction. Hypo-osmolar stress inactivates the heteromeric Kir3.4 channel expressed in Xenopus oocytes [49]. Stretch activates the cardiac G protein (GK)-gated, muscarinic K+ acetylcholine (KACh) channel if ACh is present and this appears to be independent of receptor/G protein, probably via a direct effect on the channel protein/lipid bilayer [86].

Active myofibrillar interaction, calcium and mechanoelectric transduction (Fig. 1 at 7 o'clock; Fig. 2 myofibrils – upper left quadrant)

Active myocardial contraction provides an intracellular generator of stress and strain. Stretched or isometric muscle has a short action potential duration compared with the shortening muscle [50, 64]. Moreover, isotonic (shortening) muscle, with the reduced force production, has the longer duration calcium transient. This is counter-intuitive: but a reasonable explanatory mechanism is related to force deactivation. Briefly, the reduced force with the shortening muscle reduces the affinity of troponin c for calcium [8, 64] (see also [121], and [10, 108]). This reduced calcium buffering allows intracellular calcium to rise in the face of a reduced force production. The raised calcium would influence transmembrane currents to prolong the action potential duration. For example via electrogenic Na/Ca exchange (Fig. 2 bi-directional arrow in 11 o'clock direction. These calcium aspects, also important in arrhythmogenesis (see below), have been reviewed [10] and includes mechanical influences on Sarcoplasmic Reticulum (SR) calcium cycling (see also [36, 66, 102, 103]).

Facilitators of MMC

Mechanically Mediated Crosstalk, if a tenable hypothesis, may well need systems to facilitate its integrative functions. If some of these could be identified, it could strengthen the tenant.

Calcium and cell signal cascades (Fig. 1 at 6 o'clock; Fig. 2 centre)

Mechano-chemical processes often interact with mechanoelectric and signalling processes, with calcium as an interlink. A mechanical perturbation can induce a Ca rise [10, 100]. However, mechanical stimulation releases a multitude of other second messengers [70, 97] represented in figure 2 ("cog" East of 3 o`clock – "kinase" at centre) that includes tyrosine kinase, [96] cAMP [43, 116], inositol trisphosphate [89] (Fig. 2 bottom quadrant, right), arachidonic acid [56, 57, 85]. It also activates mechanisms involving G protein [6, 59], and phospholipase C (Fig. 2 at 4 o'clock). PKC (Fig. 2, 3 o'clock) (bio)physically translocates from the cytosol, under the influence first of DAG and then of RACK in the membrane, to bring it to its target protein, allowing MAPk to switch on IEGs. More detailed individual mechano-chemo-sensitivity, including ionic currents carried by channels other than stretch-activated ones, has been reviewed [15].

Crosstalk could also be provided by AT2 and ET1 receptors, (Fig. 2 at 5 o'clock) - see also brief overview [63]) which would affect PLC via Gq (Fig. 2 at 4 o clock). This can alter intracellular Ca, first, via IP3 and SR Ca release, and second, through PLC to facilitate membrane translocation (DAG/RACK/PKC – Fig. 1 at 3 o'clock) to influence Na/H exchange, and so intracellular Ca via Na/Ca exchange (Fig. 2 at 1 o'clock).

Cytoskeleton, "tensegrity": A MMC vehicle? (Figs. 1 at 6 o'clock and 2 at 6 o'clock)

Mechanotransduction appears to involve, or to be modulated by, the intracellular cytoskeleton, and its insertions into the surrounding cell membrane via focal adherence complexes. From the electrophysiological aspect the cytoskeleton may be important because, physiologically and geometrically, parts of the cytoskeleton are associated with ion channel function [13, 14, 15, 90]. Many stimuli (Fig. 2) share intracellular signal pathways with mechano-electrochemical ones, and this can produce composite responses. Here the role of the intracellular cytoskeleton appears to be crucial. It can form the mechanical engineering and biochemical basis for intracellular and intercellular crosstalk. Any membrane channel associated with the cytoskeleton could provide a candidate for crosstalk. Stress-strain could be transmitted to the channel via the cytoskeleton to activate it, or the cytoskeleton could somehow shield the channel from the mechanical transmission of strain via other paths. The ATP activated potassium (KATP) channel, which is mechanosensitive, is attached to the cytoskeleton. Several ion channels are regionally fixed in the membrane [37], and their modulation by the cytoskeleton is also possible.

Under physiological conditions, the mechanical interconnecting system is pre-stressed, conferring mechanical balance and stability. This has been described as "tensegrity" [47], and there is thus a clear line of force communication from the extracellular matrix to intracellular cytoplasmic structures [114]. Mechanical stimuli can provoke changes in adhesions between the cell and the extracellular matrix via the fibronectin and collagen networks. In this way, mechanically distorting one cell can raise intracellular Ca2+ of its neighbouring cell [100].

The elaborate adhesion complex [40, 119] also contains focal adhesion kinase (Fig. 2 at 12 and 6 o'clock). This kinase can be the initiator or modulator of many downstream cell signals and kinases, including tyrosine kinase [87] and the renin angiotensin system (Fig. 2 at 5 o'clock) as reviewed by [97]. These are possible/probable mechanisms whereby chronic stretch can produce remodelling and hypertrophy.

MMC in the intact heart: Regulation of cardiac function

So far, the observations above, at the cellular and intracellular level, are in keeping with the presented MMC concept. If so, they should find expression at "higher" levels. Spatially, the integrative stress/strain system transmits to the whole heart. This would be by cell attachment through the adherence proteins to the extracellular matrix, which connects cells to each other. Forces at one end of a group of cells are thus transmitted throughout the organ, invoking tensegrity. This provides a clear mechanism by which a mechanically induced functional crosstalk can occur in the intact heart. Additionally, the heart is part of a hydrodynamic system. MMC in the intact heart could be via a mechanical, hydraulically mediated mechanism. That is, pressure volume changes in a system containing incompressible blood could provide the Mechanically Mediated Crosstalk. Systemic arterial pressure, and or venous volume changes can influence cardiac electrophysiology and function [15, 21, 24, 32, 33, 62, 99]. This would invoke the variety of cellular mechanisms covered above.

We know that stretch can raise heart rate by mechanisms other than neural reflexes. Sinoatrial stretch in isolated perfused hearts increases heart rate (Bainbridge, 1915; Blinks, 1956), probably by a mechano-electric mechanism [83] working through stretch activated channels and increasing the slope of the diastolic depolarisation. Thus, in addition to nervous reflex mechanisms, cellular mechanoelectric transduction provides integrative control mechanisms for raising heart rate in response to an increased venous return to the heart.

On a marginally different track, one of the major mechanosensitive regulatory mechanisms in heart is related to contractile function per se. Myocardial stretch increases force production. This has been well studied, including the pioneering work of Frank, Starling, Patterson in the intact ventricle. The prevailing dogma for the familiar Starling's Law of the Heart is a length/force sensitivity of the contractile proteins – perhaps related to calcium [1, 54]. A membrane mechanosensitivity probably also makes a contribution in the intact ventricle by mechanotransduction, possibly via stretch activated channels [28]. Studies at the membrane level corroborate this, showing that stretch can raise intracellular calcium by affecting mechanosensitive channels [10, 67, 100, 117], and so increase force.

MMC and pathophysiology (Fig. 1 at 5 o'clock)

As with other physiological integrative regulatory systems in heart, if MMC functions similarly, derangements in function should produce pathophysiological situations. Mechanoelectric feedback and its crosstalk, perhaps acting as a homeostatic feedback control system in the normal situation [63], is amplified in cardiac pathology [11, 46, 76, 91, 109, 115, 122]. The feedback is now a destabilising mechanism, because the crosstalk interactions have altered their interactive "gains". The tentative argument is that it is this derangement in crossstalk in arrhythmic death that provides the lethal expression of MMC.

Intracellular calcium changes have a pivotal role in crosstalk between intracellular signals and the generation of arrhythmia [25, 69, 78, 79]. Sustained [Ca]i increases promote [Ca]i oscillations [2] and electro-physiological oscillations are conducive to arrhythmia. Calcium is heavily involved in mechanoelectric feedback as alluded above and as reviewed by Calaghan and White [10]. Calcium changes could be pivotal in mechanically linked crosstalk during electrophysiological derangement in myocardial pathology.

MMC and mechanical components in arrhythmia

Mechanoelectric feedback/transduction is increasingly being highlighted as a possible cause of sudden cardiac arrhythmic death in man, and there are clear correlations with ventricular ejection fraction, which is a purely mechanical rather than electrophysiological predictor [19, 52, 77].

Many clinical correlates with lethal arrhythmia have their equivalent in mechanoelectric feedback in pathological mechanical changes, which produce electrical changes. At one extreme, this would be ischemically induced dyskinesia or infarction with localised stretch in the affected part of the ventricular wall. Mechanoelectric dispersion, and thus arrhythmogenic electrical dispersion, would be gross. At the other end, remodelling would produce less mechanoelectric dispersion, but, nonetheless a potentially grave one, perhaps because of its patchy nature.

MMC and the neuro-humoral component in arrhythmia

β Blockade (Fig. 1 at 9 o'clock; Fig. 2 at 11 o'clock)

One of the few therapeutic agents reducing mortality from sudden (arrhythmic) death in many subsets of patients and in related experimental situations are the β blockers. Study in this area is already voluminous, rising exponentially and a few recent reviews and studies are included here [12, 44, 53, 93, 98, 101, 110, 118]. The clinical situations covered include, infarction, hypertension, subaortic stenosis, cardiomyopathy, mitral valve prolapse, congestive cardiac failure. Moreover, depleting endogenous catecholamines by bretylium tosylate is one method for treating clinical arrhythmia [3, 16, 30, 58, 112, 113].

Although the mechanism of the therapeutic efficacy may well be due to a combination of direct anti-ischemic effects and preservation of vagal tone, all the above observations have elements of MMC. First, many of the clinical conditions associated with the autonomic nervous system and arrhythmia are associated with abnormal mechanical loads or wall motion. Secondly, the clinically related observations are in keeping with the mechanoelectric studies illustrated above. That is, electrophysiology can be modified by autonomic agonists/antagonists. Moreover, bretylium tosylate, analogous to its therapeutic effects in abating clinical arrhythmia, curtails stretch arrhythmia [28]. We need a note of caution, for the action of bretylium may be directly electrophysiological [80].

MMC and the Renin-Angiotensin system (Fig. 2 at 5 o'clock)

It is likely that the Renin Angiotensin system displays cross-talk with mechanotransduction, either by its action as a load-reducing peripheral vasodilator, or at the cell signal transduction level [31]). Either crosstalk mechanism could affect arrhythmia. Clinical trials have suggested that the reduction in sudden arrhythmic death observed with Angiotensin Converting Enzyme (ACE) inhibitors may be related to its load reducing actions on electrophysiology (see reviews in this area [24, 92, 94]. That is, by its action in reducing wall stress/strain [18]. However, cell signal crosstalk can also explain this effect, and this could be related to ACE inhibitor's slowing of cardiac remodelling. Cardiovascular drugs, such as the ACE inhibitors, and carvedilol (possessing β blocker activity); which interact with the remodelling of heart have proved their efficacy in term of cardiovascular mortality, antiarrhythmic action and prevention of sudden deaths.

MMC and hypokalaemia

Diuretic therapy in patients can reduce serum potassium, which can be arrhythmogenic [39, 88, 104], although interaction with other factors may be important [22]. Electrolyte depletion has been considered a risk factor [82]. Hypokalaemia can be related to experimental mechanotransduction [26, 32, 48]. For example, arrhythmia was generated in isolated heart, normally perfused, by increasing ventricular load. Perfusion with low potassium solutions increased the incidence/severity of this mechanically induced arrhythmia.

Longer term mechanoelectric changes

The foregoing perusal of observations supporting the existence of some sort of Mechanically Mediated Crosstalk focus mainly on the acute, short term. The question arises as to whether there are longer term manifestations.

MMC and ischemic preconditioning

Ischemic preconditioning is a consequence of a short period of ischaemia protecting the myocardium from the damage produced by a subsequent more prolonged period of ischaemia. Stretch also seems to induce preconditioning [81]. This may be related to activation of adenosine receptors, (KATP) channels, and/or PKC. In one study, 5 min ischaemia, and 5 minutes reperfusion induced ischemic preconditioning. However, a transient volume overload can also produce a "mechanical" preconditioning. The infarct size-reducing effect of stretch, with no ischemia, was prevented by the stretch channel blocker Gd3+, and Glibencamide. This means that activation of mechanosensitive ion channels may produce an analogue of ischemic preconditioning - probably by downstream activation of PKC, adenosine receptors, and/or KATP channels [41].

Remodelling and cardiac failure (Fig. 1 at 5 o'clock; Fig. 2 bottom right quadrant)

Chronic increase in load produces cascades leading to hypertrophy and remodelling. Intracellular calcium, cell signals and the cytoskeleton would be possible contenders in the cascades, which inevitably experience crosstalk (see for example, [9]), switching on immediate early genes.

Myocardial failure with a dilated, stretched heart is associated with sudden arrhythmic death. In keeping with the altered interactive gains in the pathological situation alluded to above, studies at the membrane level show, strikingly, that SACs are persistently activated in heart failure [17]. Moreover, mechanosensors are thought to be responsible for the downstream molecular changes [97] in remodelling ventricular structure and function in heart failure (Fig. 2, "Kinase" (e.g. MAPK, tyrosine kinase) to IEG). This remodelling involves a crosstalk between several cellular mechanisms, which may also be conducive to arrhythmia, as early onset genes are turned on in parallel with changes in electrophysiology [74]. It appears that in the longer term, load-induced remodelling in global myocardial failure can produce subtler but significant mechanical heterogeneity, crosstalk, and thus electrophysiological heterogeneity, which is arrhythmogenic.

Conclusion and perspectives

In summary, the existence of some type of Mechanically Mediated Crosstalk in heart has no shortage of observations supporting it as a hypothesis. Mechanosensitivity (mechanoelectric feedback or transduction) has several putative paths for crosstalk. The mechanically mediated crosstalk embraces a plethora of channels, exchangers, and cell "signalsomes". This is at a molecular, cellular, micro and macro level. This crosstalk can be spatio-temporal. It has the possibility of becoming deranged, this derangement contributing to mortality; but within MMC there is a deluge of potential therapeutic targets.

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