Biomedical subjects

Roel van der Nagel

Publications and source records attributed to Roel van der Nagel.

4 recordsLinked to original sources

PubMed2006

EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant.

OBJECTIVES: The purpose of this study was to identify apoptosis-inducing factor (AIF) as a cardiac mitochondrial antioxidant and assess the efficacy of EUK-8, a salen-manganese catalytic free radical scavenger, to protect the AIF-deficient myocardium against pressure overload. BACKGROUND: Oxidative stress has been postulated to provoke cell death and pathologic remodeling in heart failure. We recently characterized the apoptosis-inducing factor-deficient harlequin (Hq) mouse mutant to display excessive pressure overload-induced oxidative stress, cell death, accelerated progression to heart failure, and a reduced capacity of subsarcolemmal mitochondria to scavenge free radicals, suggesting a role for AIF as a novel mitochondrial antioxidant. METHODS: Oxidative stress-sensitized Hq mutant mice and their wild-type (WT) counterparts were given low-dose EUK-8 (25 mg/kg/day), an antioxidant with superoxide dismutase, catalase, and oxyradical scavenging properties, or vehicle for 4 weeks, and subjected to pressure overload (transverse aortic constriction) for 4 weeks. Myocardial geometry and function was serially assessed by echocardiography. RESULTS: EUK-8 ameliorated survival in Hq and WT mice subjected to pressure overload. EUK-8 also improved left ventricular end-systolic dimensions and fractional shortening, prevented myocardial oxidant stress, attenuated necrotic and apoptotic cell death, and attenuated cardiac hypertrophy and fibrosis in both mutant and WT mice. CONCLUSIONS: The protection against pressure overload-induced heart failure in Hq mice by EUK-8 substantiates the notion that AIF functions as an important mitochondrial antioxidant in the heart. Furthermore, because antioxidant treatment protected both the oxidative stress-prone Hq mouse model and WT mice against pressure overload-induced maladaptive left ventricular remodeling and cardiac decompensation, it may be useful as a novel therapeutic tool in the treatment of human heart failure.

Animals↗

PubMed2006

MEF2 activates a genetic program promoting chamber dilation and contractile dysfunction in calcineurin-induced heart failure.

BACKGROUND: Hypertrophic growth, a risk factor for mortality in heart disease, is driven by reprogramming of cardiac gene expression. Although the transcription factor myocyte enhancer factor-2 (MEF2) is a common end point for several hypertrophic pathways, its precise cardiac gene targets and function in cardiac remodeling remain to be elucidated. METHODS AND RESULTS: We report the existence of synergistic interactions between the nuclear factor of activated T cells and MEF2 transcription factors triggered by calcineurin signaling. To circumvent the embryonic lethality and mitochondrial deficiency associated with germ-line null mutations for MEF2C and MEF2A respectively, we used conditional transgenesis to express a dominant-negative form of MEF2 in the murine postnatal heart and combined this with magnetic resonance imaging to assess MEF2 transcriptional function in Ca2+/calcineurin-induced cardiac remodeling. Surprisingly, end-diastolic and end-systolic ventricular dimensions and contractility were normalized in the presence of severely hypertrophied left ventricular walls on MEF2 inhibition in calcineurin transgenic mice. In line, we generated lines of transgenic mice expressing MEF2A in the heart, which displayed primarily chamber dilation. Microarray profiling indicated that MEF2 promotes a gene profile functioning primarily to or at the nucleus, cytoskeletal and microtubular networks, and mitochondria. CONCLUSIONS: These findings assign a novel function to MEF2 transcription factors in the postnatal heart, where they activate a genetic program that minimally affects cardiac growth yet promotes chamber dilation, mechanical dysfunction, and dilated cardiomyopathy.

Animals↗

PubMed2005

Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure.

Abnormalities in intracellular calcium release and reuptake are responsible for decreased contractility in heart failure (HF). We have previously shown that cardiac ryanodine receptors (RyRs) are protein kinase A-hyperphosphorylated and depleted of the regulatory subunit calstabin-2 in HF. Moreover, similar alterations in skeletal muscle RyR have been linked to increased fatigability in HF. To determine whether restoration of calstabin binding to RyR may ameliorate cardiac and skeletal muscle dysfunction in HF, we treated WT and calstabin-2-/- mice subjected to myocardial infarction (MI) with JTV519. JTV519, a 1,4-benzothiazepine, is a member of a class of drugs known as calcium channel stabilizers, previously shown to increase calstabin binding to RyR. Echocardiography at 21 days after MI demonstrated a significant increase in ejection fraction in WT mice treated with JTV519 (45.8 +/- 5.1%) compared with placebo (31.1 +/- 3.1%; P < 0.05). Coimmunoprecipitation experiments revealed increased amounts of calstabin-2 bound to the RyR2 channel in JTV519-treated WT mice. However, JTV519 did not show any of these beneficial effects in calstabin-2-/- mice with MI. Additionally, JTV519 improved skeletal muscle fatigue in WT and calstabin-2-/- mice with HF by increasing the binding of calstabin-1 to RyR1. The observation that treatment with JTV519 improved cardiac function in WT but not calstabin-2-/- mice indicates that calstabin-2 binding to RyR2 is required for the beneficial effects in failing hearts. We conclude that JTV519 may provide a specific way to treat the cardiac and skeletal muscle myopathy in HF by increasing calstabin binding to RyR.

Analysis of Variance↗

PubMed2005

Downregulation of apoptosis-inducing factor in harlequin mutant mice sensitizes the myocardium to oxidative stress-related cell death and pressure overload-induced decompensation.

Apoptosis-inducing factor (AIF), or programmed cell death 8 (Pdcd8), is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal apoptosis induced by oxidative stress. Conversely, in vitro, AIF has been demonstrated to have a proapoptotic role when, on induction of the mitochondrial death pathway, AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. To determine the role of AIF in myocardial apoptotic processes, we examined cardiomyocytes from an AIF-deficient mouse mutant, Harlequin (Hq). Hq mutant cardiomyocytes demonstrated increased sensitivity to H2O2-induced cell death. Further, Hq hearts subjected to ischemia/reperfusion revealed more cardiac damage and, unlike wild-type mice, the amount of damage increased with the age of the animal. Aortic banding caused enhanced hypertrophy, increased cardiomyocyte apoptotic and necrotic cell death, and accelerated progression toward maladaptive left ventricular remodeling in Hq mutant mice compared with wild-type counterparts. These findings correlated with a reduced capacity of subsarcolemmal mitochondria from Hq mutant hearts to scavenge free radicals. Together, these data demonstrate a critical role for AIF as a cardiac antioxidant in the protection against oxidative stress-induced cell death and development of heart failure induced by pressure overload.

Animals↗