Cardiac mechanotransduction: from sensing to disease and treatment

doi:10.1016/S0165-6147(00)01679-5

Trends in Pharmacological Sciences

Volume 22, Issue 5, 1 May 2001, Pages 254-260

https://doi.org/10.1016/S0165-6147(00)01679-5 Get rights and content

Abstract

In heart muscle a mechanical stimulus is sensed and transformed into adaptive changes in cardiac function by a process called mechanotransduction. Adaptation of heart muscle to mechanical load consists of neurohumoral activation and growth, both of which decrease the initial load. Under prolonged overload this process becomes maladaptive, leading to the development of left ventricular hypertrophy and ultimately to heart failure. Widespread synergism and crosstalk among a variety of molecules and signals involved in hypertrophic signaling pathways make the prevention or treatment of left ventricular hypertrophy and heart failure a challenging task. Therapeutic strategies should include either a complete and continuous reduction of load or normalization of left ventricular mass by interventions aimed at specific targets involved in mechanotransduction.

Section snippets

Stretch-sensitive molecular elements in cardiac myocytes

In cardiac myocytes, Ca²⁺ defines contractile function but also serves as a second messenger that is able to control many other cellular functions (Fig. 1, Fig. 2). Therefore, it is not surprising that early events induced by mechanical stretch of cardiac muscle include an increase of contraction force, partly caused by an increase of the systolic Ca²⁺ transients ¹. The nonselective cation channels that can be activated by longitudinal stretch of the cells ² could be the possible stretch

Decoding the load signal

Because stretch promotes changes in [Ca²⁺]_i, recent advances have focused on enzymatic pathways (e.g. kinases and phosphatases) that could decode (Fig. 1) the load-induced changes in the amplitude or frequency of Ca²⁺ transients. Several potential Ca²⁺ decoders are activated by the intracellular Ca²⁺-binding protein calmodulin (CaM). Overexpression of CaM in transgenic mice hearts promotes hypertrophy ¹¹, and α-adrenoceptor stimulation-induced hypertrophy can be inhibited by the CaM antagonist

Physiological feedback mechanisms decreasing the load signal

An essential part of cardiac mechanotransduction is the activation of neurohormonal mechanisms that increase myocardial contractility and decrease hemodynamic load (Fig. 1). One main feedback mechanism suppressing the load signal is formed by the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are synthesized, stored and released from atrial and ventricular tissue in response to increased wall stretch ²⁹. These hormones bind to specific receptors

From signaling to gene transcription

Transcription factors that regulate gene expression are among the targets of load-activated kinases and phosphatases (Fig. 4). Binding sites for several transcription factors, including transcriptional enhancer factor 1 (TEF-1), activating protein 1 (AP-1) and serum response element (SRE), might be important in mediating the in vitro response to hypertrophic signals in neonate cardiocyte cultures ³⁸. Whether these findings reflect the in vivo situation of the hypertrophied adult heart is not

Current treatment strategy

The management of heart failure with left ventricular hypertrophy and systolic dysfunction includes the combined use of angiotensin converting enzyme (ACE) inhibitors, β-adrenoceptor blockers, diuretics and digoxin. This strategy improves the prognosis in heart failure with ACE inhibitors 51, 52 and β-adrenoceptor blockers 53, 54, and spironolactone in advanced heart failure ⁵⁵. Despite recent developments in the pharmacological treatment of hypertension, the common cause of hypertrophy, the

Future perspectives

To date, it has been demonstrated that myocardial stretch rapidly activates a plethora of intracellular signaling pathways (Fig. 1, Fig. 2, Fig. 3). When seeking the signal cascade from stretch to altered gene expression, myocyte hypertrophy and heart failure, simple mechanisms, with one event leading to another in a precise manner, are not likely to be found. It is more probable that the development of the hypertrophy includes synergism of signal pathways (Fig. 4). Increased understanding of

Acknowledgements

We thank Andrew French and Olli Vuolteenaho for valuable comments on the manuscript. This work was supported by Academy of Finland, Sigrid Juselius Foundation, Wihuri Foundation, Finnish Foundation for Cardiovascular Research and Paavo Nurmi Foundation.

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This chapter highlights the major progress that has been achieved in studies of mechanosensitive (MS) ion channels from prokaryotic and eukaryotic cells whose molecular identity has been elucidated to date. The first part focuses on mechanotransduction in microbial and plant cells and briefly describes the structure, function, gating mechanism, and pharmacology of two major types of MS channels of large and small conductance that are present in these cells. The second part focuses on diversity of stretch-activated (SA) channels that have been identified to play a role in mechanosensory transduction in animal cells. This part highlights the role of the lipid bilayer and the cytoskeleton as well as interaction of extracellular matrix components with eukaryotic MS ion channels. The chapter also describes mechanosensitivity of cells from various tissues, including nervous system, cochlea, skin skeletal muscle, bone and cartilage, heart and blood vessels. Furthermore, it refers briefly to the role that SA channels may play in the pathology of diseases, including neuronal and cardiovascular pathophysiology.
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Trends in Pharmacological Sciences

ReviewCardiac mechanotransduction: from sensing to disease and treatment

Abstract

Section snippets

Stretch-sensitive molecular elements in cardiac myocytes

Decoding the load signal

Physiological feedback mechanisms decreasing the load signal

From signaling to gene transcription

Current treatment strategy

Future perspectives

Acknowledgements

Biochem. Biophys. Res. Commun.

J. Mol. Cell Cardiol.

Trends Pharmacol. Sci.

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J. Mol. Cell. Cardiol.

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Review
Cardiac mechanotransduction: from sensing to disease and treatment

Mechanisms of stretch-induced changes in [Ca²⁺]_i in rat atrial myocytes: role of increased troponin C affinity and stretch-activated ion channels

Changes in force and cytosolic Ca²⁺ concentration after length changes in isolated rat ventricular trabeculae

Mechanisms underlying the increase in force and Ca²⁺ transient that follow stretch of cardiac muscle: a possible explanation of the Anrep effect

Functional InsP₃ receptors that may modulate excitation–contraction coupling in the heart

The effect of Ca²⁺–calmodulin-dependent protein kinase II on cardiac excitation–contraction coupling in ferret ventricular myocytes

Signal transduction in atria and ventricles of mice with transient cardiac expression of activated G protein α_q