![]() In contrast, the work of Ohler et-al (2009) showed no significant change in the structure of t-system between isolated normal and failing cardiomyocytes by using 2-photon imaging of di-8-ANNEPs labeling. Recently the work of Lyon et-al (2009) using scanning ion conductance microscopy and confocal imaging of di-8-ANNEPs labeling suggested a loss of t-system structure in isolated failing human cardiomyocytes. Despite the importance of the t-system in calcium handling, few studies have examined the organization of the t-system in normal and failing human myocardium although t-tubule-related structures are known to be changed. Dyssynchronous or non-uniform CICR associated with a change in t-tubule organisation has also been observed in murine, canine and porcine models of heart failure.Ĭa 2+ handling abnormalities have been described in various forms of human heart failure including idiopathic dilated cardiomyopathy (IDCM). The idea that microscopic structural alterations in the organization of DHPRs and RyRs within the couplon might play a role in heart failure was first raised in a computer modelling study and this idea has gained traction from rodent studies that have detected a reduced ability of the L-type Ca 2+ current to trigger CICR. It is unclear whether these alterations in t-tubule density result in a reduction in couplon density, although such an effect might help explain reduced contractility in heart failure. In a dog model of heart failure, a reduction in t-tubule density was observed, and similar alterations have been reported in other heart failure animal models (see below). The t-tubules form a network of plasma membrane invaginations, , and in human ventricular myocytes, couplons have a transverse spacing of ∼0.8 µm. The transverse tubular system (t-tubules) of cardiac ventricular myocytes enables highly synchronized calcium release by CICR at couplons. The close and precise alignment of DHPRs and RYRs in a structure called the “couplon” is thought to be critical to efficient CICR. The SR release forms Ca 2+sparks which summate to produce the cell-wide increase in Ca 2+ which regulates force. In CICR, the action potential opens L-type calcium channels (dihydropyridine receptors -DHPRs) in the surface membrane and t-tubular membranes to activate the sarcoplasmic reticulum (SR) ryanodine receptors (RyRs) to cause release of Ca 2+ from the SR. In longitudinal (but not transverse) sections there was an ∼30% reduction in the degree of colocalization between DHPRs and RyRs as measured by Pearson's correlation coefficient in failing hearts.Įxcitation-contraction coupling (ECC) in cardiac ventricular muscle occurs via the calcium induced calcium release (CICR) mechanism (for review see ). The general relationship between DHPRs and RyR was not changed and RyR labeling overlapped with 51☓% of DHPR labeling in normal hearts. There was no change in the fractional area occupied by myofilaments (labeled with phalloidin) but there was a small reduction in the number of RyR clusters per unit area. In failure, dilation of peripheral t-tubules occurred and a change in the extent of protein glycosylation was evident. Wheat germ agglutinin (WGA), Na-Ca exchanger, DHPR and caveolin-3 labels revealed a shift from a predominantly transverse orientation to oblique and axial directions in failing myocytes. ![]() The organization of t-tubules, L-type calcium channels (DHPRs), ryanodine receptors (RyRs) and contractile machinery were examined in fixed ventricular tissue samples from both normal and failing hearts (idiopathic (non-ischemic) dilated cardiomyopathy) using high resolution fluorescent imaging. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |