Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Abstract

BackgroundFollowing pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction.Methods and ResultsSprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2).ConclusionsAfter pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.

Quantitative Temporal Analysis of Protein Dynamics in Maladaptive Cardiac Remodeling

“…A rate of protein synthesis that is higher than the degradation rate while the level of NSPs is declining suggests an imbalance of mitochondrial homeostasis, with many dysfunctional proteins as well as impaired oxidative capacity in the face of high energy. These data fall in line with observations in HF patients and post-infarct mice with cardiac remodeling (Murphy, Ardehali et al 2016, Chaanine, Sreekumaran Nair et al 2017). Mitochondrial proteins may have a higher synthesis than degradation rate in MCR (scenario 2 in Table 1 ); however, both the synthesis and degradation rates are most likely much lower compared to the sham group, clarifying the lower levels of NSPs.…”

“…Our data also reveal that the majority (50%) of the protein dynamics detected is relevant to the biological processes of oxidative phosphorylation and mitochondrial function (Figures 4A and 4B); these proteins exhibited decreased levels of NSPs in parallel to a rate of protein synthesis greater than that of protein degradation (increased protein turnover rate, scenario 2 in Table 1 ). Perturbations in mitochondrial homeostasis and metabolism are essential mechanisms in the pathophysiology of cardiac remodeling and HF (Chaanine, Sreekumaran Nair et al 2017). Previous observations suggest that mitochondrial biogenesis, signaling, and oxidative capacity are preserved or increased in the early stages of cardiac remodeling in order to match the energy demand imposed by a detrimental stressor such as ISO.…”

“…Previous observations suggest that mitochondrial biogenesis, signaling, and oxidative capacity are preserved or increased in the early stages of cardiac remodeling in order to match the energy demand imposed by a detrimental stressor such as ISO. Subsequently, the transition to MCR and HF corresponds to a decrease in mitochondrial biogenesis and oxidative metabolism (Chaanine, Sreekumaran Nair et al 2017). In our data, we observe a decreased level of NSPs involved in oxidative phosphorylation, but these proteins exhibited an increased rate of protein turnover.…”

In Silico Analysis of Differential Gene Expression in Three Common Rat Models of Diastolic Dysfunction

“…Evidence was recently reported that endothelial Tspan5- and Tspan17-ADAM10 complexes contribute to inflammation by maintaining VE-cadherin expression and promoting T lymphocyte transmigration ( 78 ). Another injury-related gene that was upregulated was BNIP3 , which is associated with mitochondrial autophagy and apoptosis and is increased in the heart by pressure overload and various stresses ( 79 , 80 ).…”

Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice

“…The decreased mitochondria content is also in line with the severe myocardial fibrosis observed in these mice. In this context, it is noteworthy that the development of DCM with eccentric remodeling after left ventricular overload has been shown to result in enhanced mitochondrial apoptosis and impaired mitochondrial function which, however, only took place after a post-intervention period of eight weeks in healthy rats [33]. Moreover, decreases in respiratory chain function after pressure overload to the heart only take place with the beginning of impaired left ventricular function [34].…”