Thin myofilament proteins in norm and heart failure I. Polymerizability of myocardial Straub actin in acute and chronic heart failure

Abstract

The reduced and intrinsic viscosities of myocardial Straub F-actin from the left ventricle of a practically healthy man were equal to 3.05 +/- 0.2 and 2.4 +/- 0.32 and from the right ventricle were 2.37 +/- 0.2 and 2.1 +/- 0.3 dl/g, respectively (the difference between ventricles was not significant). The average length of filaments measured by flow birefringence technique was equal to 1.3 +/- 0.04 micron, the number-average length (Ln), determined by the electron microscopy was 1.4 micron, the weight-average length (Lw), was 2 microns and the maximal one was 5.5 microns. The histograms showed that the most characteristic length was that of 0.8-1.2 micron. According to the flow birefringence data canine myocardial F-actin had a length similar to that of myocardial F-actin from a practically healthy man, though its reduced and intrinsic viscosities were higher. In acute and especially chronic congestive heart failure the actin polymerizability was sharply reduced. In consequence, in acute heart failure the number-average length of F-actin filaments was decreased by 43% and in congestive heart failure by 65.7%. The characteristic length in acute heart failure shifts to the range of 0.2-0.6 micron, while in congestive heart failure the range is 0.2-0.4 micron. This fact can possibly explain why during preparation of actin from the pathologically changed myocardium according to the methods including purification by the cycles of polymerization-sedimentation-depolymerization, the pathologically changed actin is discarded and the normal actin remains. A definite parallel was observed between the reduction of actin polymerizability and the ability of myocardial glycerinated fiber bundles (MBGF) to generate force. We conclude that the changes of actin properties in heart failure may cause a decrease in contractibility of the myocardial contractile protein system.

Energy, structure, conformation, and heart failure

“…Despite structural stabilization and opposite deviations from normal, weakening of interdomain bonds is observed also in LTC. The mean length of F-actin filament (measured by double refraction in flow) in LTC and ATC decreases by 25 and 20%, reslSectively, in comparison with the normal level [88].…”

“…Disturbances in actin polymerization suggest that both the outer domain and the isthmus are involved in recombinant rearrangements of actin protomer [8,88]. These rearrangements lead to radial elongation of the outer domain and smoothening of the interdomain cleft; the protomer freezes and, in contrast to normal protein, does not change this conformation in either contracting, or rigor medium [35], and undergoes no force-generating conformation rearrangements.…”

“…In view of the key role of actin in force generation and impairment of SCMP contractility in HF [6,7,26,[86][87][88], we studied the structure of natural thin filament and its protomers in HF caused by athyreotic cardiomyopathy (ATC) lasting for 2-3 months [13] and TAM [33]. Electron microscopy combined with optic and computer diffraction, as well as photographic and computer-assisted filtration of diffraction pictures and microphotographs were used; computer-assisted 3-D reconstruction was carried out using the method of modifying projecting functions.…”

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

“…As a result, we found that the differential bestclassifier proteins Low-HF-active/High-HF-inactive point towards an important role for actin nucleation and polymerization mechanisms in drug response (reflected by the functions regulation of actin nucleation, regulation of Arp2/3 complex-mediated actin nucleation, SCAR complex, filopodium tip, or dendrite extension). In fact, the alteration of actin nucleation and polymerization mechanisms has been reported in heart failure [38][39][40]. Interestingly, a role for the activation of another differential best-classifier candidate, ATGR2, has been proposed to mediate some of the beneficial effects of angiotensin II receptor type 1 antagonists, such as valsartan [41,42].…”

Thermodynamic parameters of melting and stabilization of G-actin structure in the norm and cardiomyopathy

“…It was previously established that 2-3-month-long cardiac insufficiency caused by L-thyroxin-induced (LTC) and athyroid (ATC) cardiomyopathy (or myocardial dystrophy according to G. F. Lang) strongly impairs polymerization of actin in human or animal myocardium [9]. According to circular dichroism data, the conformation of G-and F-actins changes drastically [3]; hybrid actomyosin containing actin from the post mortem myocardium of a patient dead from cardiac insufficiency [8] superprecipitates (contracts [7]) much more weaker than actomyosin containing normal actin.…”