Transmural variations in gene expression of stretch-modulated proteins in the rat left ventricle

Abstract

The properties of left ventricular cardiac myocytes vary transmurally. This may be related to the gradients of stress and strain experienced in vivo across the ventricular wall. We tested the hypothesis that within the rat left ventricle there are transmural differences in the expression of genes for proteins that are involved in mechanosensitive pathways and in associated physiological responses. Real time reverse transcription polymerase chain reaction was used to measure messenger RNA (mRNA) levels of selected targets in sub-epicardial (EPI) and subendocardial (ENDO) myocardium. Carbon fibres were attached to single myocytes to stretch them and to record contractility. We observed that the slow positive inotropic response to stretch was not different between EPI and ENDO myocytes and consistent with this, that the mRNA expression of two proteins implicated in the slow response, non-specific cationic mechanosensitive channels (TRPC-1) and Na/H exchanger, were not different. However, mRNA levels of other targets, e.g. the mechanosensitive K + channel TREK-1, Brain Natriuretic Peptide and Endothelin-1 receptor B, were significantly greater in ENDO than EPI. No targets had significantly greater mRNA levels in EPI than ENDO. On the basis of these findings, we suggest that the response of the ventricle to stretch will depend upon both the regional differences in stimuli and the relative expression of the mechanosensitive targets and that generally, stretch sensitivity is predicted to be greater in ENDO.

Patterns of muscular strain in the embryonic heart wall

“…Increased force transduction by titin isoforms at higher sarcomere lengths (Linke, 2008) suggests that stress gradients may be steeper than strain gradients, as we model them assuming linear stress/strain relations. Stretch sensitivity has been implicated in several molecular concomitants of hypertrophy in mammals (Liang and Gardner, 1998; Ergul et al, 2000; Palmieri et al, 2002; Pikkarainen et al, 2003, 2006; Ennis et al, 2005; Lemmens et al, 2006; Stones et al, 2007). A perhaps distinct molecular consequence of strain gradients may be the redistribution and action of growth factors such as FGF-2, released by physical stretch, depleted in the inner layers of chick ventricle (Joseph-Silverstein et al, 1989), and active in local control of myocyte proliferation (Mima et al, 1995).…”

Transmural gradients of myocardial structure and mechanics: Implications for fiber stress and strain in pressure overload

“…The TREK-1 gene, mRNA, and protein expression levels were greater in endocardial cells than epicardial cells (Kelly et al, 2006), (Stones et al, 2007), (Tan et al, 2004), (Wang et al, 2013). Interestingly, the gradient of this potassium channel is in the opposite direction to that of the Kv4.2 and KChIP channels, all of which contribute to repolarization, though with differing kinetics they are responsible for acting during different portions of the action potential (Grant, 2009), (Nerbonne and Kass, 2005).…”

“…MHC-β is predominant in human hearts, whereas MHC-α is more highly expressed in rodents. Stones et al (Stones et al, 2007) measured a transmural gradient in MHC-β mRNA in rat LV, with more found in subendocardium than subepicardium. No gradient in MHC-α was found in rat ventricular myocytes (Campbell et al, 2013), but it has been shown in porcine hearts that greater expression in MHC-α isoform expression in the subepicardium contributes to differing mechanical function and timing, both of which may modify fiber stresses and strains (Stelzer et al, 2008).…”

Theoretical analysis of the adaptive contractile behaviour of a single cardiomyocyte cultured on elastic substrates with varying stiffness

“…Thus, myocytes isolated from the sub-endocardium are more responsive to stretch than those from the sub-epicardium (Stones et al, 2007), with higher passive and active tensions developed in sub-endocardium at the same sarcomere length (Cazorla et al, 2003). Considering in addition that the myocardium stiffness is modulated by the biosynthesis and organization of the collagen matrix network, this modelling approach could thus provide a starting point for an extended analysis and performance evaluation of the adaptive response of cardiomyocyte to modifications of the mechanical properties of their environment in both physiological and pathological contexts where cardiac tissue remodelling or fibrosis take place.…”