Altered tension cost in (TG(mREN-2)27) rats overexpressing the mouse renin gene

Abstract

The present study aimed to characterize cardiac hypertrophy induced by activation of the renin-angiotensin system in terms of functional alterations on the level of the contractile proteins, employing transgenic rats harboring the mouse renin gene (TGR(mREN2)27). Ca2+-dependent tension and myosin ATPase activity were measured in skinned fiber preparations obtained from TGR(mREN2)27 and from age-matched Sprague-Dawley rats (SPDR). Western blots for troponin I (TnI) and troponin T (TnT) were performed and the phosphorylation status of TnI were evaluated in myocardial preparations. TnT and myosin heavy chain (MHC) isoforms were analyzed by RT-PCR. The pCa/tension relationship was shifted to the right in TGR(mREN2)27 compared to SPDR as indicated by increased Ca2+-concentrations required for half maximal activation of tension (SPDR 5.80, 95% confidence limits 5.77-5.82 vs. TGR(mREN2)27 5.69, 95% confidence limits 5.67-5.72, pCa units), while maximal developed tension was unaltered. Even more pronounced was the shift in the relationship between pCa and myosin-ATPase (SPDR 6.01, 95% confidence limits 5.99-6.03 vs. TGR(mREN2)27 5.77, 95% confidence limits 5.73-5.79, pCa units). The maximal myosin-ATPase activity was reduced in TGR(mREN2)27 compared to SPDR, respectively (211.0 +/- 28.77 micromol ADP/s vs. 271.6 +/- 43.66 micromol ADP/s, P < 0.05). Tension cost (ATPase activity/tension) was significantly reduced in TGR(mREN2)27. The beta-MHC expression was significantly increased in TGR(mREN2)27. There was no isoform shift for TnT (protein and mRNA), as well as TnI, and no alteration of the phosphorylation of TnI in TGR(mREN2)27 compared to SPRD. The present study demonstrates that cardiac hypertrophy, induced by an activation of the renin-angiotensin system, leads to adapting alterations on the level of the contractile filaments, which reduce tension cost.

Depressed myocardial cross-bridge cycling kinetics in a female guinea pig model of diastolic heart failure

“…That is, we found reduced force-dependent ATP consumption rate (tension-cost), reduced force redevelopment rate (K tr ), and prolongation of myofilament relaxation time (Time lin ). We and others have previously reported similar findings in rat models of cardiac disease ( Daniels et al, 2007 ; Zobel et al, 2007 ; Patel et al, 2017 ). However, as discussed above, a significant shift in myosin isoform expression is seen in this species during cardiac stress ( Daniels et al, 2007 ).…”

“…α-MHC is the faster molecular motor, displaying three- to fivefold faster actin-activated ATPase activity, time to peak systole, shortening velocity, and cross-bridge cycling kinetics compared with β-MHC ( van der Velden et al, 1998 ; Rundell et al, 2005 ; Locher et al, 2009 ; Chen et al, 2010 ; Locher et al, 2011 ; de Tombe and ter Keurs, 2012 ). Most of the studies documenting depressed cross-bridge cycling kinetics in the failing heart have been done either in rats or mice ( Rundell et al, 2004 ; Daniels et al, 2007 ; Zobel et al, 2007 ; Patel et al, 2017 ). Rats and mice almost exclusively express the alpha isoform of myosin (α-MHC) in their ventricles.…”

Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat

“…The Ren2 model develops cardiac hypertrophy that leads to adaptive alterations in the level of the contractile filaments (56). The increase in ␤-myosin heavy chain expression (56) may partially be responsible for the observed LV diastolic dysfunction in the Ren2 heart.…”

Chronic high‐dose testosterone treatment: impact on rat cardiac contractile biology

“…The decrease in cross-bridge kinetics could be another representation of the development of cardiac pathology. Although a lower tension-cost indicates more efficient ATP utilization (Rundell et al, 2004;Rundell et al, 2005), decreased tension-cost has also been found in many pathological models (Rundell et al, 2004;Zobel et al, 2007).…”