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Lai-Hua Xie

Bio: Lai-Hua Xie is an academic researcher from Rutgers University. The author has contributed to research in topics: Afterdepolarization & Mitochondrial permeability transition pore. The author has an hindex of 39, co-authored 118 publications receiving 4808 citations. Previous affiliations of Lai-Hua Xie include Rutgers Biomedical and Health Sciences & University of California, Los Angeles.


Papers
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Journal ArticleDOI
TL;DR: This study modified the L-type calcium (Ca) current and Ca(i) cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, and developed a minimal seven-state Markovian model of I(Ca,L) that reproduced Ca- and voltage-dependent kinetics.

393 citations

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TL;DR: How the cardiovascular system is controlled and influenced by not only a unique intrinsic system, but is also heavily influenced by the autonomic nervous system as well as the endocrine system is reviewed.
Abstract: The function of the heart is to contract and pump oxygenated blood to the body and deoxygenated blood to the lungs. To achieve this goal, a normal human heart must beat regularly and continuously for one's entire life. Heartbeats originate from the rhythmic pacing discharge from the sinoatrial (SA) node within the heart itself. In the absence of extrinsic neural or hormonal influences, the SA node pacing rate would be about 100 beats per minute. Heart rate and cardiac output, however, must vary in response to the needs of the body's cells for oxygen and nutrients under varying conditions. In order to respond rapidly to the changing requirements of the body's tissues, the heart rate and contractility are regulated by the nervous system, hormones, and other factors. Here we review how the cardiovascular system is controlled and influenced by not only a unique intrinsic system, but is also heavily influenced by the autonomic nervous system as well as the endocrine system.

361 citations

Journal ArticleDOI
Takahiro Ishii1, Makoto Takano1, Lai-Hua Xie1, Akinori Noma1, Harunori Ohmori1 
TL;DR: Results indicate that HAC4 formsI f in rabbit heart SA node, which encodes the hyperpolarization-activated cation channel (I for I h) by screening a rabbit sinoatrial node cDNA library using a fragment of rat brain cDNA.

289 citations

Journal ArticleDOI
TL;DR: H2O2-induced afterdepolarizations depend on both impaired INa inactivation to reduce repolarization reserve and enhancement of ICa,L to reverse repolarizations, which are both facilitated by CaMKII activation.
Abstract: In the heart, oxidative stress caused by exogenous H 2 O 2 has been shown to induce early afterdepolarizations (EADs) and triggered activity by impairing Na current ( I Na ) inactivation. Because H 2 O 2 activates Ca 2+ /calmodulin kinase (CaMK)II, which also impairs I Na inactivation and promotes EADs, we hypothesized that CaMKII activation may be an important factor in EADs caused by oxidative stress. Using the patch-clamp and intracellular Ca (Ca i ) imaging in Fluo-4 AM–loaded rabbit ventricular myocytes, we found that exposure to H 2 O 2 (0.2 to 1 mmol/L) for 5 to 15 minutes consistently induced EADs that were suppressed by the I Na blocker tetrodotoxin (10 μmol/L), as well as the I Ca,L blocker nifedipine. H 2 O 2 enhanced both peak and late I Ca,L , consistent with CaMKII-mediated facilitation. By prolonging the action potential plateau and increasing Ca influx via I Ca,L , H 2 O 2 -induced EADs were also frequently followed by DADs in response to spontaneous (ie, non– I Ca,L -gated) sarcoplasmic reticulum Ca release after repolarization. The CaMKII inhibitor KN-93 (1 μmol/L; n=4), but not its inactive analog KN-92 (1 μmol/L, n=5), prevented H 2 O 2 -induced EADs and DADs, and the selective CaMKII peptide inhibitor AIP (autocamtide-2–related inhibitory peptide) (2 μmol/L) significantly delayed their onset. In conclusion, H 2 O 2 -induced afterdepolarizations depend on both impaired I Na inactivation to reduce repolarization reserve and enhancement of I Ca,L to reverse repolarization, which are both facilitated by CaMKII activation. Our observations support a link between increased oxidative stress, CaMKII activation, and afterdepolarizations as triggers of lethal ventricular arrhythmias in diseased hearts.

254 citations

Journal ArticleDOI
TL;DR: Investigation of the role of intracellular calcium (Ca2+i) cycling in regulating APD restitution slope and repolarization alternans in patch-clamped rabbit ventricular myocytes found it requires intact Ca2-i cycling and is not reliably predicted by APd restitution slope when Ca2+ i cycling is suppressed.
Abstract: Action potential duration (APD) restitution properties and repolarization alternans are thought to be important arrhythmogenic factors. We investigated the role of intracellular calcium (Ca2+i) cycling in regulating APD restitution slope and repolarization (APD) alternans in patch-clamped rabbit ventricular myocytes at 34 to 36 degrees C, using the perforated or ruptured patch clamp techniques with Fura-2-AM to record Ca2+i. When APD restitution was measured by either the standard extrastimulus (S1S2) method or the dynamic rapid pacing method, the maximum APD restitution slope exceeded 1 by both methods, but was more shallow with the dynamic method. These differences were associated with greater Ca2+i accumulation during dynamic pacing. The onset of APD alternans occurred at diastolic intervals at which the APD restitution slope was significantly <1 and was abolished by suppressing sarcoplasmic reticulum (SR) Ca2+i cycling with thapsigargin and ryanodine, or buffering the global Ca2+i transient with BAPTA-AM or BAPTA. Thapsigargin and ryanodine flattened APD restitution slope to <1 when measured by the dynamic method, but not by the S1S2 method. BAPTA-AM or BAPTA failed to flatten APD restitution slope to <1 by either method. In conclusion, APD alternans requires intact Ca2+i cycling and is not reliably predicted by APD restitution slope when Ca2+i cycling is suppressed. Ca2+i cycling may contribute to differences between APD restitution curves measured by S1S2 versus dynamic pacing protocols by inducing short-term memory effects related to pacing-dependent Ca2+i accumulation.

251 citations


Cited by
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Journal ArticleDOI
TL;DR: This text is a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA.
Abstract: The text consists of two sections, one for those studying or practicing diagnostic radiology, nuclear medicine and radiation oncology; the other for those engaged in the study or clinical practice of radiation oncology--a new chapter, on radiologic terrorism, is specifically for those in the radiation sciences who would manage exposed individuals in the event of a terrorist event. The 17 chapters in Section I represent a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA. The 11 chapters in Section II address more in-depth topics in radiation oncology, such as cancer biology, retreatment after radiotherapy, chemotherapeutic agents and hyperthermia.

1,359 citations

Journal ArticleDOI
TL;DR: The crystal structure of different Kir channels is opening the way to understanding the structure-function relationships of this simple but diverse ion channel family.
Abstract: Inwardly rectifying K+ (Kir) channels allow K+ to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are ...

1,286 citations

Journal ArticleDOI
TL;DR: The relation between the biophysical properties of recombinant HCN channels and the pattern of HCN mRNA expression with the properties of native Ih in neurons and cardiac muscle is reviewed.
Abstract: Hyperpolarization-activated cation currents, termed If, Ih, or Iq, were initially discovered in heart and nerve cells over 20 years ago. These currents contribute to a wide range of physiological functions, including cardiac and neuronal pacemaker activity, the setting of resting potentials, input conductance and length constants, and dendritic integration. The hyperpolarization-activated, cation nonselective (HCN) gene family encodes the channels that underlie Ih. Here we review the relation between the biophysical properties of recombinant HCN channels and the pattern of HCN mRNA expression with the properties of native Ih in neurons and cardiac muscle. Moreover, we consider selected examples of the expanding physiological functions of Ih with a view toward understanding how the properties of HCN channels contribute to these diverse functional roles.

1,095 citations

Journal ArticleDOI
TL;DR: A model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is developed and experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undISEased human myocytes were quantitatively reproduced by the model.
Abstract: Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.

1,012 citations

Journal ArticleDOI
TL;DR: The review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer, and report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.
Abstract: Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.

1,004 citations