Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro

Izumi, Toshiaki; Kihara, Yasuki; Sarai, Nobuaki; Yoneda, Tomohiro; Iwanaga, Yoshitaka; Inagaki, Kenji; Onozawa, Yoko; Takenaka, Hiroyuki; Kita, Toru; Noma, Akinori

doi:10.1161/01.cir.0000096484.03318.ab

Cited by 60 publications

(42 citation statements)

References 34 publications

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“…31 In addition, angiotensin II also exerts direct cellular electrophysiological effects on cardiomyocytes that favor the development of AF. 32 Experimental studies have shown that angiotensin II modulate the expression of multiple ion channels, including the L-type and T-type calcium current (I Ca, T , I Ca, L ), 33,34 the rapid and slow component of the delayed rectifier potassium currents (I Ks , I Kr ), 35 and the transient outward potassium current (I to ). 36 These changes in the expression of ion channels as well as alteration of calcium handling in atrial cardiomyocytes can promote the development of AF.…”

Section: Raas Activationmentioning

confidence: 99%

Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications

Yiu

Siu

et al. 2011

J Hum Hypertens

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Hypertension is one of the most important risk factors associated with atrial fibrillation (AF) and increased the risk of cardiovascular events in patients with AF. However, the pathophysiological link between hypertension and AF is unclear. Nevertheless, this can be explained by the hemodynamic changes of the left atrium secondary to long standing hypertension, resulting in elevated left atrium pressure and subsequently left atrial enlargement. Moreover, the activation of renin --angiotensin --aldosterone system (RAAS) activation in patients with hypertension induces left atrial fibrosis and conduction block in the left atrium, resulting in the development of AF. Accordingly, recent studies have shown that effective blockage of RAAS by angiotensin converting enzyme inhibitors or angiotensin receptor antagonist may be effective in both primary and secondary prevention of AF in patients with hypertension, although with controversies. In addition, optimal antithrombotic therapy, blood pressure control as well as rate control for AF are key to the management of patients with AF. 1,2 Both hypertension 3 and AF 4 have increased frequency with the ageing population worldwide, and are associated with increased cardiovascular events. They are important risk factors for stroke, heart failure and overall mortality. 5 --7 On the other hand, hypertension is one of the important risk factors for the occurrence of AF, 8 and increased the risk of stroke and cardiovascular mortality in patients with AF.9,10 Compare with other risk factors for AF, hypertension appears to be responsible for more AF than any other risk factor because of its high prevalence. However, the pathophysiological link between AF and hypertension remains unclear. Moreover, it is also unclear whether treatment of hypertension prevents AF or reduces the risk of AF related complications. The purpose of this article is to review the epidemiology, underlying mechanisms and therapeutic implications of AF in hypertensive patients. A systematic literature search for full-text papers in the English language was performed using MEDLINE, Embase and the Cochrane library through to July 2011. In the search phrases used, the following terms were used: 'atrial fibrillation', 'hypertension', 'epidemiology', 'pathophysiology' and 'treatment'. Papers selected and cited in this review were based on the authors' view on the relevance to the manuscript. In addition, abstracts from international cardiovascular meetings were studied to identify unpublished studies.

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Section: Raas Activationmentioning

confidence: 99%

Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications

Yiu

Siu

et al. 2011

J Hum Hypertens

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“…Reexpression of T-type current has also been reported in pressure-overloaded rat and mouse hearts, in many different models of heart failure, and after myocardial infarction injury (12)(13)(14)(15)(16). More recently, reinduction of T-type current in the failing rat heart was shown to be dependent on endothelin-1 signaling (17). Reexpression of T-type current in the diseased myocardium conducts additional Ca 2+ influx during the action potential, although the function of this Ca 2+ influx remains unknown.…”

Section: Introductionmentioning

confidence: 99%

α1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

Nakayama

Bódi²,

Correll³

et al. 2009

J. Clin. Invest.

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In noncontractile cells, increases in intracellular Ca 2+ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca 2+ -dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca 2+ serves as a second messenger given the high Ca 2+ concentrations that control contraction. T-type Ca 2+ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of α1G, which generates Ca v 3.1 current, to investigate whether this type of Ca 2+ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, α1G transgenic mice showed no cardiac pathology despite large increases in Ca 2+ influx, and they were even partially resistant to pressure overload-, isoproterenol-, and exercise-induced cardiac hypertrophy. Conversely, α1G -/-mice displayed enhanced hypertrophic responses following pressure overload or isoproterenol infusion. Enhanced hypertrophy and disease in α1G -/-mice was rescued with the α1G transgene, demonstrating a myocyte-autonomous requirement of α1G for protection. Mechanistically, α1G interacted with NOS3, which augmented cGMP-dependent protein kinase type I activity in α1G transgenic hearts after pressure overload. Further, the anti-hypertrophic effect of α1G overexpression was abrogated by a NOS3 inhibitor and by crossing the mice onto the Nos3 -/-background. Thus, cardiac α1G reexpression and its associated pool of T-type Ca 2+ antagonize cardiac hypertrophy through a NOS3-dependent signaling mechanism.

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“…low-voltage-activated calcium channel; oxidative stress; cardiomyocytes SINCE THE INITIAL BIOPHYSICAL (34) and molecular characterization (5, 27, 36) of low-voltage-activated T-type calcium currents in heart and neurons, these channels have been studied in various systems and pathological conditions. T-type currents are reexpressed in the adult hypertrophied ventricle and in postmyocardial infarction (18), in the monocrotaline model of pulmonary hypertension and heart failure (24,44), and in vitro in adult ventricular myocytes exposed to 10% FBS (9) and endothelin-1 (19), relating the T-type current to the pathology rather than to normal physiological function of the myocytes. The mechanisms for regulation of the T-type channels are incompletely characterized, largely due to the lack of specific inhibitors and the presence of the more robust L-type and store-operated calcium channels, which make it difficult to isolate T-type Ca 2ϩ channel functions, such as secretion (29), excitation (52), or transcription regulation (4).…”

mentioning

confidence: 99%

“…Less is known about the pathways involved in Ca v 3.1 ␣-subunit regulation, although there is evidence that Ca v 3.1 mRNA is increased in adult ventricular myocytes exposed to endothelin-1 (19). Also, heterologously expressed Ca v 3.1 membrane currents can be increased when coexpressed with the L-type calcium channel auxiliary ␣ 2 ␦-subunit (13) or decreased by the ␥ 6 -subunit (16).…”

mentioning

confidence: 99%

T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes

Pluteanu

Cribbs

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Pluteanu F, Cribbs LL. T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes. Am J Physiol Heart Circ Physiol 297: H1304 -H1313, 2009. First published August 7, 2009 doi:10.1152/ajpheart.00528.2009.-Low-voltageactivated calcium channels are reexpressed in ventricular myocytes in pathological conditions associated with hypoxic episodes, but a direct relation between oxidative stress and T-type channel function and regulation in cardiomyocytes has not been established. We aimed to investigate low-voltage-activated channel regulation under oxidative stress in neonatal rat ventricular myocytes. RT-PCR measurements of voltage-gated Ca 2ϩ (Cav)3.1 and Cav3.2 mRNA levels in oxidative stress were compared with whole cell patch-clamp recordings of T-type calcium current. The results indicate that hypoxia reduces T-type current density at Ϫ30 mV (the hallmark of this channel) based on the shift of the voltage dependence of activation to more depolarized values and downregulation of Ca v3.1 at the mRNA level. Upon reoxygenation, both Ca v3.1 mRNA levels and the voltage dependence of total T-type current are restored, although differently for activation and inactivation. Using Ni 2ϩ , we distinguished different effects of hypoxia/reoxygenation on the two current components. Long-term incubation in the presence of 100 M CoCl 2 reproduced the effects of hypoxia on T-type current activation and inactivation, indicating that the chemically induced oxidative state is sufficient to alter T-type calcium current activity, and that hypoxia-inducible factor-1␣ is involved in Ca v3.1 downregulation. Our results demonstrate that Ca v3.1 and Cav3.2 T-type calcium channels are differentially regulated by hypoxia/reoxygenation injury, and, therefore, they may serve different functions in the myocyte in response to hypoxic injury. low-voltage-activated calcium channel; oxidative stress; cardiomyocytes SINCE THE INITIAL BIOPHYSICAL (34) and molecular characterization (5, 27, 36) of low-voltage-activated T-type calcium currents in heart and neurons, these channels have been studied in various systems and pathological conditions. T-type currents are reexpressed in the adult hypertrophied ventricle and in postmyocardial infarction (18), in the monocrotaline model of pulmonary hypertension and heart failure (24, 44), and in vitro in adult ventricular myocytes exposed to 10% FBS (9) and endothelin-1 (19), relating the T-type current to the pathology rather than to normal physiological function of the myocytes. The mechanisms for regulation of the T-type channels are incompletely characterized, largely due to the lack of specific inhibitors and the presence of the more robust L-type and store-operated calcium channels, which make it difficult to isolate T-type Ca 2ϩ channel functions, such as secretion (29), excitation (52), or transcription regulation (4).

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Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro

Cited by 60 publications

References 34 publications

Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications

Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications

α1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes

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