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Biomedical subjects

Andrew R Marks

Publications and source records attributed to Andrew R Marks.

At least 37 records · Page 2Linked to original sources
PubMed2005

Ryanodine receptor-targeted anti-arrhythmic therapy.

Cardiac arrhythmia is an important cause of death in patients with heart failure (HF) and inherited arrhythmia syndromes, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Alterations in intracellular calcium handling play a prominent role in the generation of arrhythmias in the failing heart. Diastolic calcium leak from the sarcoplasmic reticulum (SR) via cardiac ryanodine receptors (RyR2) may initiate delayed afterdepolarizations and triggered activity leading to arrhythmias. Similarly, SR Ca(2+) leak through mutant RyR2 channels may cause triggered activity during exercise in patients with CPVT. Novel therapeutic approaches, based on recent advances in the understanding of the cellular mechanisms underlying arrhythmias in HF and CPVT, are currently being evaluated to specifically correct defective Ca(2+) release in these lethal syndromes.

Anti-Arrhythmia Agents↗
PubMed2004

Calstabin deficiency, ryanodine receptors, and sudden cardiac death.

Altered cardiac ryanodine receptor (RyR2) function has an important role in heart failure and genetic forms of arrhythmias. RyR2 constitutes the major intracellular Ca2+ release channel in the cardiac sarcoplasmic reticulum (SR). The peptidyl-prolyl isomerase calstabin2 (FKBP12.6) is a component of the RyR2 macromolecular signaling complex. Calstabin2 binding to RyR2 is regulated by PKA phosphorylation of Ser2809 in RyR2. PKA phosphorylation of RyR2 decreases the binding affinity for calstabin2 and increases RyR2 open probability and sensitivity to Ca2+-dependent activation. In heart failure, a majority of studies have found that RyR2 becomes chronically PKA hyper-phosphorylated which depletes calstabin2 from the channel complex. Calstabin2 dissociation causes a diastolic SR Ca2+ leak contributing to depressed intracellular Ca2+ cycling and decreased cardiac contractility. Missense mutations linked to genetic forms of exercise-induced arrhythmias and sudden cardiac death also cause decreased calstabin2-binding affinity and leaky RyR2 channels. We review the importance of calstabin2 for RyR2 function and excitation-contraction coupling, and discuss new observations that implicate dysregulation of calstabin2 binding as a central mechanism for abnormal calcium cycling in heart failure and triggered arrhythmias.

Animals↗
PubMed2004

Overexpression of beta2-adrenergic receptors cAMP-dependent protein kinase phosphorylates and modulates slow delayed rectifier potassium channels expressed in murine heart: evidence for receptor/channel co-localization.

The cardiac slow delayed rectifier potassium channel (IKs), comprised of (KCNQ1) and beta (KCNE1) subunits, is regulated by sympathetic nervous stimulation, with activation of beta-adrenergic receptors PKA phosphorylating IKs channels. We examined the effects of 2-adrenergic receptors (beta2-AR) on IKs in cardiac ventricular myocytes from transgenic mice expressing fusion proteins of IKs subunits and hbeta2-ARs. KCNQ1 and beta2-ARs were localized to the same subcellular regions, sharing intimate localization within nanometers of each other. In IKs/B2-AR myocytes, IKs density was increased, and activation shifted in the hyperpolarizing direction; IKs was not further modulated by exposure to isoproterenol, and KCNQ1 was found to be PKA-phosphorylated. Conversely, beta2-AR overexpression did not affect L-type calcium channel current (ICaL) under basal conditions with ICaL remaining responsive to cAMP. These data indicate intimate association of KCNQ1 and beta2-ARs and that beta2-AR signaling can modulate the function of IKs channels under conditions of increased beta2-AR expression, even in the absence of exogenous beta-AR agonist.

Animals↗
PubMed2004

Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.

BACKGROUND: Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart. METHODS AND RESULTS: Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function. CONCLUSIONS: Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.

Adult↗
PubMed2004

Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.

Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.

Animals↗
PubMed2004

Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor.

The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Using site-directed mutagenesis, we identified the specific Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation site on recombinant RyR2, distinct from the site for protein kinase A (PKA) that mediates the "fight-or-flight" stress response. CaMKII phosphorylation increased RyR2 Ca2+ sensitivity and open probability. CaMKII was activated at increased heart rates, which may contribute to enhanced Ca2+-induced Ca2+ release. Moreover, rate-dependent CaMKII phosphorylation of RyR2 was defective in heart failure. CaMKII-mediated phosphorylation of RyR2 may contribute to the enhanced contractility observed at higher heart rates. The full text of this article is available online at http://circres.ahajournals.org.

Adrenergic beta-Agonists↗
PubMed2004

Regulation of the type 1 inositol 1,4,5-trisphosphate receptor by phosphorylation at tyrosine 353.

The inositol 1,4,5-trisphosphate receptor (IP3R) plays an essential role in Ca2+ signaling during lymphocyte activation. Engagement of the T cell or B cell receptor by antigen initiates a signal transduction cascade that leads to tyrosine phosphorylation of IP3R by Src family nonreceptor protein tyrosine kinases, including Fyn. However, the effect of tyrosine phosphorylation on the IP3R and subsequent Ca2+ release is poorly understood. We have identified tyrosine 353 (Tyr353) in the IP3-binding domain of type 1 IP3R (IP3R1) as a phosphorylation site for Fyn both in vitro and in vivo. We have developed a phosphoepitope-specific antibody and shown that IP3R1-Y353 becomes phosphorylated during T cell and B cell activation. Furthermore, tyrosine phosphorylation of IP3R1 increased IP3 binding at low IP3 concentrations (<10 nm). Using wild-type IP3R1 or an IP3R1-Y353F mutant that cannot be tyrosine phosphorylated at Tyr353 or expressed in IP3R-deficient DT40 B cells, we demonstrated that tyrosine phosphorylation of Tyr353 permits prolonged intracellular Ca2+ release during B cell activation. Taken together, these data suggest that one function of tyrosine phosphorylation of IP3R1-Y353 is to enhance Ca2+ signaling in lymphocytes by increasing the sensitivity of IP3R1 to activation by low levels of IP3.

Binding Sites↗
PubMed2004

Molecular determinants of altered contractility in heart failure.

Heart failure remains a leading cause of mortality in the Western world. An important hallmark of heart failure is reduced myocardial contractility. Alterations in intracellular Ca2+ handling play a major role in the pathophysiology of these contractile abnormalities. Several defects in the excitation-contraction (EC) coupling system have been identified in patients with heart failure. Alterations in the density and function of proteins relevant for EC coupling have been reported. Chronic stimulation of the beta-adrenergic signaling pathway leads to protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2), which dissociates FKBP12.6 from RyR2, thereby altering channel gating and promoting diastolic sarcoplasmic reticulum (SR) Ca2+ release. This may deplete the SR Ca2+ stores, which may reduce myocardial contractility. Clinical studies have demonstrated that beta-adrenergic receptor blockers reduce morbidity and mortality in all grades of congestive heart failure. Our experimental data indicate that beta-blockers reverse RyR2 hyperphosphorylation and normalize channel gating, which is associated with increased contractility in heart failure. In conclusion, chronic hyperactivity of the beta-adrenergic signaling pathway impairs intracellular Ca2+ handling, which leads to reduced contractility in patients with heart failure.

Adrenergic beta-Agonists↗
PubMed2004

Drug-eluting stents.

Advances in catheter and stent design have made stent implantation the standard coronary angioplasty procedure. Unfortunately, in-stent restenosis continues to plague this procedure, with the optimum binary restenosis rates reaching ~10% to 20%. In the past few years, it has become clear that in-stent restenosis is largely due to the migration and proliferation of vascular smooth muscle cells to form a neointima. To address this issue, stents coated with drug-delivery vehicles have been developed to deliver antiproliferative therapeutics. Two drugs, rapamycin and taxol, have been the lead compounds for testing the idea of a drug-eluting stent. These drugs have been successful largely because of the solid mechanistic understanding of their effects and extensive preclinical examination. The result of these years of work is that the rapamycin-coated stent entered the US market in April of 2003, and the taxol-coated stent appears poised to follow soon.

Drug Delivery Systems↗
PubMed2004

The economy of science.

We are in the midst of an era of plummeting pay lines at the NIH. History shows that when the federal deficit is high, NIH pay lines tend to fall, and the impact on biomedical research can be disastrous. Equally bad is the disincentive for the future generations of biomedical researchers who observe their mentors struggling to get adequate funding. How many bright young people will be turned away from careers in biomedical research? How much innovative science will be delayed or never initiated, how many new cures never realized? At a time of unprecedented challenges and remarkable technological advances that enable us to address those challenges, lack of funding is a threat to our society.

Biomedical Research↗
PubMed2004

Blasts from the past.

With this issue of the JCI, we celebrate the 80th anniversary of the Journal. While 80 years is not a century, we still feel it is important to honor what the JCI has meant to the biomedical research community for 8 decades. To illustrate why the JCI is the leading general-interest translational research journal edited by and for biomedical researchers, we have asked former JCI editors-in-chief to reflect on some of the major scientific advances reported in the pages of the Journal during their tenures.

Animals↗
PubMed2004

Lost gold: the decline of the academic mission in US medical schools.

Medical education needs to be redesigned so that it is an equally shared responsibility of clinicians and physician-scientists, with greatly enhanced opportunities for student-faculty bonding. Traditional departments and divisions must be restructured to provide more thoughtful and effective support for academic clinicians and physician-scientists. Existing infrastructure should be improved so that in exchange for the commitment of time and effort for teaching, the faculty members receive tangible services from their institutions (e.g., information technology that actually saves time, state-of-the art teaching aids that are user friendly, streamlined administrative oversight to avoid duplicate submissions to regulatory offices, more helpful grant management and accounting).

Curriculum↗
PubMed2004

Cardiac ryanodine receptor function and regulation in heart disease.

The cardiac ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR) controls intracellular Ca(2+) release and muscle contraction in the heart. Ca(2+) release via RyR2 is regulated by several physiological mediators. Protein kinase (PKA) phosphorylation dissociates the stabilizing FKBP12.6 subunit (calstabin2) from the RyR2 complex, resulting in increased contractility and cardiac output. Congestive heart failure is associated with elevated plasma catecholamine levels, and chronic stimulation of beta-adrenergic receptors leads to PKA hyperphosphorylation of RyR2 in failing hearts. PKA hyperphosphorylation results in calstabin2-depleted RyR2 that displays altered channel gating and may cause aberrant SR Ca(2+) release, depletion of SR Ca(2+) stores, and reduced myocardial contractility in heart failure. Calstabin2-depleted RyR2 may also trigger cardiac arrhythmias that cause sudden cardiac death. In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), RyR2 missense mutations cause reduced calstabin2 binding to RyR2. Increased RyR2 phosphorylation and pathologically increased calstabin2 dissociation during exercise results in aberrant diastolic calcium release, which may trigger ventricular arrhythmias and sudden cardiac death. In conclusion, heart failure and exercise-induced sudden cardiac death have been linked to defects in RyR2-calstabin2 regulation, and this may represent a novel target for the prevention and treatment of these forms of heart disease.

Heart Diseases↗
PubMed2003

The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages.

Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterol-loaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop-/- macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.

Animals↗
PubMed2003

FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.

Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.

Animals↗