Transmural stretch-dependent regulation of contractile properties in rat heart and its alteration after myocardial infarction

Abstract : The " stretch-sensitization " response is essential to the regulation of heart contractility. An increase in diastolic volume improves systolic contraction. The cellular mechanisms of this modulation, the Frank-Starling law, are still uncertain. Moreover, their alterations in heart failure remains controversial. Here, using left ventricular skinned rat myocytes, we show a nonuniform stretch-sensitization of myofilament activation across the ventricular wall. Stretch-dependent Ca 2+ sensitization of myofilaments increases from sub-epicardium to sub-endocardium and is correlated with an increase in passive tension. This passive tension-dependent component of myofibrillar activation is not associated with expression of titin isoforms, changes in troponin I level, and phosphorylation status. Instead, we observe that stretch induces phosphorylation of ventricular myosin light chain 2 isoform (VLC2b) in sub-endocardium specifically. Thus, VLC2b phosphorylation could act as a stretch-dependent modulator of activation tuned within normal heart. Moreover, in postmyocardial infarcted rat, the gradient of stretch-dependent Ca 2+ sensitization disappears associated with a lack of VLC2b phosphorylation in sub-endocardium. In conclusion, nonuniformity is a major characteristic of the normal adult left ventricle (LV). The heterogeneous myocardial deformation pattern might be caused not only by the morphological heterogeneity of the tissue in the LV wall, but also by the nonuniform contractile properties of the myocytes across the wall. The loss of a contractile transmural gradient after myocardial infarction should contribute to the impaired LV function. Key words: Ca 2+ sensitization • Frank-Starling law • ventricular myocytes • myosin light chain 2 • heart failure eart muscle has the property to develop positive inotropism in response to an increase in end-diastolic ventricular volume. This phenomenon, known as the Frank-Starling law, originates from cell adaptation to stretch involving a sarcomere length (SL) dependence of the Ca 2+ sensitivity of myofilament activation (1). The mechanisms that underlie this intrinsic property may involve a length-dependent increase in the affinity of the regulatory site of troponin H
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Olivier Cazorla, Szabolcs Szilagyi, Jean-Yves Le Guennec, Guy Vassort, Alain Lacampagne. Transmural stretch-dependent regulation of contractile properties in rat heart and its alteration after myocardial infarction. FASEB Journal, Federation of American Society of Experimental Biology, 2005, 19 (1), pp.88-90. ⟨10.1096/fj.04-2066fje⟩. ⟨hal-01824390⟩

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