Potential Role of BNIP3 in Cardiac Remodeling, Myocardial Stiffness, and Endoplasmic Reticulum

Chaanine, Antoine H.; Gordon, Ronald E.; Kohlbrenner, Erik; Bénard, Ludovic; Jeong, Dongtak; Hajjar, Roger J.

doi:10.1161/circheartfailure.112.000200

Cited by 83 publications

(80 citation statements)

References 28 publications

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“…Moreover, the proper placement/position of the clip was verified and clip internalization within the aortic lumen, with aneurysmal growth of the aorta around it, was excluded in all animals at the end of the hemodynamic study after euthanasia of the animal. In previous studies,11, 12 a 1.5‐mm 2 size clip resulted in substantial early mortality and a high (but not invariant) rate of progression to eccentric remodeling (ER) and marked systolic dysfunction at 8 weeks post‐AAB. Thus, here we utilized a larger clip (2.0 mm 2 ) to produce less severe POL and a milder phenotype allowing elucidation of differences in phenotypic response to POL.…”

Section: Methodsmentioning

confidence: 93%

“…If such (likely) modest differences were critical to our observations, a highly specific stress set point for triggering pathologic hypertrophic remodeling would be suggested. This is unlikely given that phenotypic variability was also seen in studies using a tighter vascular clip 11. Differences in activity among animals may contribute to the cumulative severity of cardiac stress and contribute to variability, but activity patterns were not assessed.…”

Section: Discussionmentioning

confidence: 99%

“…Based on our previous experience with the rat AB model using a smaller vascular clip,11 we anticipated that use of a larger vascular clip would produce slightly less severe POL with lower early mortality but would retain the phenotypical variability we had previously observed but not systematically studied. Thus, a large (n=68) albeit somewhat arbitrary number of rats were subjected to banding.…”

Section: Methodsmentioning

confidence: 99%

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

Chaanine

Nair

Bergen

et al. 2017

JAHA

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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.

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Section: Methodsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Chaanine

Nair

Bergen

et al. 2017

JAHA

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“…Ca 2+ may be a key regulator between ERS and heart failure. Chaanine et al [137] reported that in a rat model of pressure overload-induced heart failure, calcium shifted from the ER to mitochondrial compartments, leading to a decrease in ER calcium content, mitochondrial damage, cells apoptosis and LV interstitial fibrosis, hence contributing to both systolic and diastolic myocardial dysfunction. In systolic heart failure, SERCA2α downregulation, along with Bcl-2/adenovirus E1B19 kd-interacting protein 3 (BNIP3) upregulation, exacerbate myocardial diastolic and systolic dysfunction.…”

Section: Endoplasmic Reticulum Stress Is Involved In the Development mentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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“…25 We, therefore, examined the effect of hypertrophy and GW7647 treatment on SERCA2 levels in neonatal hearts. A hypertrophy-mediated decrease in SERCA2 protein expression was seen in the LV, but not in the RV ( Figure 5A).…”

Section: Gw7647 Treatment Activates Calciumhandling Proteins Reducesmentioning

confidence: 99%

Activating PPARα Prevents Post–Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts

Lam

Zhang

Huqi

et al. 2015

Circulation Research

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Rationale: Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid β-oxidation rates.Objective: We determined whether stimulating fatty acid β-oxidation with GW7647, a peroxisome proliferatoractivated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. Methods and Results:Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid β-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. Conclusions:

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Potential Role of BNIP3 in Cardiac Remodeling, Myocardial Stiffness, and Endoplasmic Reticulum

Cited by 83 publications

References 28 publications

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

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

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

Activating PPARα Prevents Post–Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts

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