Increased Na+/Ca2+ Exchanger Expression/Activity Constitutes a Point of Inflection in the Progression to Heart Failure of Hypertensive Rats

Abstract

Spontaneously hypertensive rat (SHR) constitutes a genetic model widely used to study the natural evolution of hypertensive heart disease. Ca2+-handling alterations are known to occur in SHR. However, the putative modifications of Ca2+-handling proteins during the progression to heart failure (HF) are not well established. Moreover, the role of apoptosis in SHR is controversial. We investigated intracellular Ca2+, Ca2+-handling proteins and apoptosis in SHR vs. control Wistar rats (W) from 3 to 15 months (mo). Changes associated with the transition to HF (i.e. lung edema and decrease in midwall fractional shortening), occurred at 15 mo in 38% of SHR (SHRF). In SHRF, twitch and caffeine-induced Ca2+ transients, significantly decreased relative to 6/9 mo and 15 mo without HF signs. This decrease occurred in association with a decrease in the time constant of caffeine-Ca2+ transient decay and an increase in Na+/Ca2+ exchanger (NCX) abundance (p<0.05) with no changes in SERCA2a expression/activity. An increased Ca2+-calmodulin-kinase II activity, associated with an enhancement of apoptosis (TUNEL and Bax/Bcl2) was observed in SHR relative to W from 3 to 15 mo. Conclusions: 1. Apoptosis is an early and persistent event that may contribute to hypertrophic remodeling but would not participate in the contractile impairment of SHRF. 2. The increase in NCX expression/activity, associated with an increase in Ca2+ efflux from the cell, constitutes a primary alteration of Ca2+-handling proteins in the evolution to HF. 3. No changes in SERCA2a expression/activity are observed when HF signs become evident.

Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive—A New Preclinical Model

“…Notably, no functional difference in Na + /Ca 2+ current density was detected between HHR and NHR cardiomyocytes. This contrasts with previous experimental demonstration of Na + /Ca 2+ exchanger upregulation as a key process in transition to failure in HFrEF . These findings also differ from observations made in a setting of diastolic dysfunction where the primary insult is acute renal intervention (nephrectomy) and cardiomyocyte systolic Ca 2+ levels and contractility are unchanged .…”

“…There was no evidence of HHR‐specific low‐voltage activated currents (absence of inflexion in current plots from −115 and −90 mV holding potentials) (Figure ). Capacity for Ca 2+ flux via the Na + /Ca 2+ exchanger was examined electrophysiologically, as this transporter upregulation is implicated in arrhythmogenicity . In forward mode operation (ie, Ca 2+ extrusion, inward current, from −90 mV) and reverse mode operation (to +40 mV), the I‐NCX densities (pA/pF) were not different for NHR and HHR (Figure D through F).…”

“…Capacity for Ca 2+ flux via the Na + /Ca 2+ exchanger was examined electrophysiologically, as this transporter upregulation is implicated in arrhythmogenicity. 21 In forward mode operation (ie, Ca 2+ extrusion, inward current, from À90 mV) and reverse mode operation (to +40 mV), the I-NCX densities (pA/pF) were not different for NHR and HHR ( Figure 5D through 5F). Protein expression data indicate that NCX1 levels are also not different in the NHR and HHR ( Figure S7).…”

Low-Level Vagus Nerve Stimulation Reverses Cardiac Dysfunction and Subcellular Calcium Handling in Rats With Post-Myocardial Infarction Heart Failure

“…27) Specifically, impaired SERCA2a function and enhanced Na + /Ca 2+ exchanger (NCX) activity have been proposed as causes of reduced SR Ca 2+ load in HF. 28,29) Moreover, the role of pathological diastolic SR Ca 2+ leak via RyR2 has been recognized as an important contributor to the altered Ca 2+ handling in HF. 30,31) Similarly, rats with post-MI HF in our study showed a significant reduction in SERCA2a while the content of NCX1 was markedly increased.…”

Pivotal role of α2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease

“…B and C ) (Rodriguez et al . ). Indeed, partial NCX inhibition restores Ca 2+ signalling in myocytes from failing hearts (Hobai et al .…”