Published online before print November 24, 2008, doi: 10.1161/HYPERTENSIONAHA.108.118356
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2009;53:57.)
© 2009 American Heart Association, Inc.
Original Articles |
Activation of Endothelial Nitric Oxide Synthase by a Vanadium Compound Ameliorates Pressure Overload-Induced Cardiac Injury in Ovariectomized Rats
From the Departments of Pharmacology (M.S.B., N.S., K.F.) and Synthetic Chemistry (M.S., Y.I.), Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; and Tohoku University 21st Century Center of Excellence Program "CRESCENDO" (K.F.), Sendai, Japan.
Correspondence to Kohji Fukunaga, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan. E-mail fukunaga{at}mail.pharm.tohoku.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We here investigated the effect of bis(1-oxy-2-pyridinethiolato) oxovanadium (IV), [VO(OPT)], against myocardial hypertrophy and cardiac functional recovery in pressure overload–induced hypertrophy in ovariectomized female rats and defined mechanisms underlying its cardioprotective action. Wistar rats subjected to bilateral ovariectomy were further treated with abdominal aortic stenosis. VO(OPT) (containing 1.25 and 2.50 mg of vanadium per kg) was administered orally once a day for 14 days starting from 2 weeks after aortic banding. Treatment with VO(OPT) significantly inhibited pressure overload–induced increase both in the heart weight:body weight ratio and the lung weight:body weight ratio. VO(OPT) also attenuated hypertrophy-induced impaired left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contractility (±dp/dtmax). VO(OPT) treatment significantly restored pressure overload–induced impaired endothelial NO synthase activity with concomitant increased phosphorylation of endothelial NO synthase (Ser1179). Moreover, VO(OPT) treatment significantly restored pressure overload–induced reduced Akt activity, as indicated by increased phosphorylation at Ser473 and at Thr308. Treatment with VO(OPT) also secondarily inhibited calpastatin and dystrophin breakdown and decreased myosin light chain phosphorylation. Finally, VO(OPT) treatment significantly attenuated mortality after repeated isoproterenol administration in pressure overloaded–ovariectomized rats. Taken together, VO(OPT) attenuates cardiac myocytes hypertrophy in vivo in pressure overload–induced hypertrophy in ovariectomized rats and prevents the process from hypertrophy to heart failure. These effects are mediated by inhibition of calpastatin and dystrophin breakdown in addition to increased Akt and endothelial NO synthase activities.
Key Words: myocardial hypertrophy • protein kinase B (Akt) • endothelial nitric oxide synthase (eNOS) • ovariectomy • dystrophin
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Left ventricular (LV) hypertrophy is an independent risk factor for the development of heart failure.1 Although LV hypertrophy is an adaptive response to pressure and volume overload, this process becomes maladaptive without drug therapy. The pathological cardiac hypertrophy, in turn, triggers the development of heart failure.2 The search for novel drug treatment has directed attention to cardiac hypertrophy as cardioprotection.2
Signaling through the phosphatidylinositol 3-kinase/Akt pathway is important for the physiological growth and inhibition of pathological hypertrophy.3–5 Moreover, physiological hypertrophy induced by exercise training also requires the activation of myocardial Akt. By contrast, pathological hypertrophies induced by pressure overload cause an inactivation of the Akt signal pathway.6 We have also reported that pressure overload (PO)–induced hypertrophy in ovariectomized (OVX) female rats markedly reduces both endothelial NO synthase (eNOS) protein expression and its activity with concomitantly marked reduced Akt activity.7
Inhibition of eNOS induces myocardial hypertrophy in rats.8 Likewise, NO has antihypertrophic effects, thereby inhibiting cardiac remodeling.9,10 Increased eNOS activity by angiotensin-converting enzyme inhibitors,11 statins,12,13 and estrogens14 elicits an improvement of cardiac remodeling. Moreover, bovine eNOS is phosphorylated on Ser1179 (1177 for the human eNOS) by the Ser/Thr kinase Akt15,16 with concomitant increased NO production even at low calcium concentrations. Indeed, statins activate the serine/threonine kinase Akt in endothelial cells, thereby enhancing eNOS phosphorylation and increasing NO.3 However, drugs targeting activation of Akt have not been developed in the hypertrophy-induced cardiac remodeling. Thus, we hypothesize that stimulator of phosphatidylinositol 3-kinase/Akt signaling likely inhibits cardiac remodeling via upregulation of eNOS in the cardiomyocytes.
We17–19 and others20 have shown that vanadium compounds are potent Akt activators with cytoprotective action against myocardial ischemia/reperfusion injury. In addition, we recently introduced a novel vanadyl (IV) compound having 
O2+ chelate, bis(1-oxy-2-pyridinethiolato) oxovanadium (IV), [VO[(OPT)], as potent activator of protein kinase B/Akt, thereby protecting cardiomyocytes from ischemia/reperfusion injury in rats18 and in mouse brain ischemia.21 Consistent with our findings, the vanadyl (IV) form of vanadium possesses cardioprotective action22 and antihypertensive action in spontaneous hypertensive rats and in fructose-induced hypertensive rats23–25 through unknown mechanisms.
In the present study, we evaluated the effect of continuous treatment with VO(OPT) in PO-induced cardiac injury induced by transverse aortic constriction in OVX female rats.7 To observe the cardioprotective effect of the Akt activator VO(OPT) in the hypertrophy-induced cardiac remodeling, we used the OVX PO-induced hypertrophy model, because that model causes reproducible hypertrophy with the severe impairment of Akt and eNOS signaling.7 We also defined the molecular mechanism underlying VO(OPT)-mediated cardioprotection in LV hypertrophy and its remodeling. We especially focused on VO(OPT)-mediated activation of the myocardial Akt and eNOS signaling after PO-induced hypertrophy. Finally, we confirm VO(OPT)-induced inhibition of cardiac remodeling rescue rats from isoproterenol-induced cardiac arrest.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
For detailed Materials and Methods, please see the online data supplement, available at http://hyper.ahajournals.org.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Effect of VO(OPT) Treatment on Morphometric Changes
Averages of heart weights (HWs; including both left and right ventricle), lung weights (LWs), and body weights (BWs) are presented in Table S1. Consistent with our previous observation, LV weight (P<0.01 versus OVX) and LW (P<0.001 vs OVX) significantly increased in the OVX pressure overloaded (OVX-PO) group compared with the OVX group, without significant changes in right ventricle weight.7 Treatment with VO(OPT) (2.50 mg of vanadium per kg, PO) on the sham and OVX rats had no effect on the morphometric parameters (Table S2). Treatment with VO(OPT) significantly and dose-dependently decreased the elevated LV weights and LWs. Notably, the ratio of HW:BW markedly increased in the OVX-PO group (P<0.001 versus OVX) compared with the OVX group. Treatment with VO(OPT) (2.50 mg of vanadium per kg) significantly restored the elevated the HW:BW ratio (P<0.01 versus OVX-PO; Figure 1A). Increases in the LW:BW ratio also significantly increased in the OVX-PO group (P<0.001) compared with the OVX group. VO(OPT) treatment dose-dependently decreased the elevated LW:BW ratio (P<0.01 versus OVX-PO for 1.25 mg and P<0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 1B). Moreover, oral treatment with VO(OPT) (2.50 mg of vanadium per kg) for 14 days had no effect on the HW:BW ratio (Figure S1A) or the HW:LW ratio (Figure S1B) in sham-operated animals.
|
P<0.05 and
Effect of VO(OPT) Treatment on Hemodynamic Parameters
We documented previously that acute treatment with VO(OPT) by intraperitoneal administration has no effect on mean arterial blood pressure (MABP) and heart rate (HR).18 Here we tested continuous oral administration (14 days) of VO(OPT) on HR and MABP on both sham and OVX animals. VO(OPT) treatment (2.50 mg of vanadium per kg) slightly decreased HR in both sham and OVX rats, but changes were not significant (Figure S2A). VO(OPT) treatment (2.50 mg of vanadium per kg) slightly decreased MABP in sham rats, but a significant decrease in MABP was observed in OVX rats (Figure S2B). Consistent with a previous observation,7 OVX-PO treatment significantly increases both in HR (P<0.01 versus OVX; Figure 2A) and in MABP (P<0.01 versus OVX; Figure 2B) compared with OVX rats. VO(OPT) treatment dose-dependently and significantly reduced HR (P<0.05 versus OVX-PO for 1.25 mg and P<0.05 versus OVX-PO for 2.50 mg of vanadium; Figure 2A) and MABP (P<0.05 versus OVX-PO for 1.25 mg and P<0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 2B).
|
Because treatment with VO(OPT) (1.25 and 2.50 mg of vanadium per kg) restored HR and MABP, we evaluated LV functions in OVX-PO heart with or without treatment of VO(OPT). Consistent with our previous observation,7 LV end-diastolic pressure was significantly increased in the OVX-PO group (P<0.001 versus OVX) compared with the OVX group. VO(OPT) treatment dose-dependently restored elevated LV end-diastolic pressure (P<0.001 versus OVX-PO for 1.25 mg and P<0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 2C). Similarly, LV developed pressure significantly increased in the OVX-PO group (P<0.001 versus OVX), and VO(OPT) treatment dose-dependently restored elevated LV developed pressure (P<0.01 versus OVX-PO vehicle for 1.25 mg and P<0.001 versus OVX-PO vehicle for 2.50 mg of vanadium; Figure 2D). The rates of LV contraction (+dp/dt) and relaxation (–dp/dt) also significantly increased in OVX-PO (P<0.001 versus OVX; Figure 2E),7 and VO(OPT) treatment dose-dependently restored the elevated LV contraction (+dp/dt; P<0.001 versus OVX-PO for 1.25 mg and P<0.001 versus OVX-PO for 2.50 mg of vanadium) and relaxation (–dp/dt; P<0.05 versus OVX-PO for 1.25 mg and P<0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 2E). In agreement with earlier studies,26,27 the treatment with VO(OPT) containing 2.50 mg of vanadium per kg resulted in slight decrease in body weight and food intake compared with vehicle-treated rats (Figure S3), but these changes are not significant.
Effect of VO(OPT) Treatment on Akt Activity
To define the role of Akt activity in cardiac hypertrophy and heart failure, we evaluated the time course of cardiac hypertrophy, heart failure, and the LV Akt activity. HW:BW and LW:BW were increased time dependently from 1 to 4 weeks after PO in OVX rats (Figure S4A and S4B). LV Akt phosphorylation at Ser473 was increased 1 week after PO; thereafter, it decreased time dependently, with a significantly decreased level observed 4 weeks after PO in OVX rats. On the contrary, no significant change was observed in the total Akt level (Figure S5A). We also documented previously that OVX-PO treatment severely decreased Akt phosphorylation at Ser473 in female rats.18 Akt phosphorylation at Thr308 also slightly decreased in the OVX-PO group, but the change was not significant (Figure 3). Importantly, VO(OPT) treatment markedly and dose-dependently increased Akt activity as assessed by increased phosphorylation at Ser473 (P<0.01 versus OVX-PO for 1.25 mg and P<0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 3A and 3B) and at Thr308 (P<0.01 for 1.25 mg and P<0.001 for 2.50 mg of vanadium; Figure 3A and 3C). On the contrary, there were no significant changes in total Akt protein under these conditions (Figure 3).
|
Effect of VO(OPT) Treatment on eNOS Expression and Its Activity
Because eNOS is a physiological substrate for Akt in human vascular endothelial cells,28,29 we determined whether VO(OPT)-induced Akt activation results in increased eNOS phosphorylation and its activity. The time course studies revealed that both eNOS and Akt-mediated eNOS phosphorylation at Ser1179 decreased time dependently after PO treatment with a significantly decreased level observed 4 weeks after PO in OVX rats (Figure S5B). Consistent with our previous observation,7 we also observed severe impairment of eNOS expression after OVX-PO treatment (P<0.01 versus OVX). We found here a slight but not significant reduction of eNOS phosphorylation at Ser1179. Notably, VO(OPT) treatment dose-dependently increased eNOS phosphorylation (P<0.01 for 1.25 mg and P<0.001 for 2.5 mg of vanadium; Figure 4A and 4B). VO(OPT) also significantly increased eNOS expression (P<0.05 for 2.5 mg of vanadium; Figure 4A and 4C). These results suggests that VO(OPT) treatment preferentially activates eNOS activity through Akt-dependent phosphorylation at Ser 1179.
|
Effects of VO(OPT) Treatment on Heat Shock Protein-90 and Caveolin-3 Expression
Localization and activity of eNOS are regulated by making a complex with a chaperone protein, heat shock protein-90 (HSP-90) and caveolin-3 in cardiomyocytes, especially in caveolae.30 Because the eNOS protein level was reduced by the OVX-PO group, we assessed whether HSP-90 and caveolin-3 levels are changed by OVX-PO and whether VO(OPT) treatment affects their expression. OVX-PO treatment slightly but not significantly decreased HSP-90 expression. VO(OPT) treatment tended to recover HSP-90 expression in the LV (Figure 5A). Similarly, OVX-PO treatment did not affect the caveolin-3 expression (Figure 5B). Taken together, downregulation of eNOS was not attributable to changes in HSP-90 and caveolin-3 levels as a binding partner of eNOS in caveolae of cardiomyocytes. We documented previously a significant and marked increase in myosin light chain (MLC) phosphorylation (Ser19) in the OVX-PO group when its phosphorylation was expressed by the ratio of the phospho-MLC:total MLC.7 Interestingly, VO(OPT) treatment dose-dependently decreased MLC phosphorylation (P<0.05 versus OVX-PO for 1.25 mg and P<0.01 for 2.5 mg of vanadium; Figure 5C).
|
Effect of VO(OPT) Treatment on Calpastatin and Dystrophin Levels
Because increased MLC phosphorylation suggested increased intracellular Ca2+ concentration or inhibition of MLC phosphatase activity, we next investigated activation of calpain in OVX-PO LV muscles. OVX-PO treatment significantly induced dystrophin breakdown, which is a substrate for calpain in the pathological conditions (P<0.05 versus OVX; Figure 6A). More importantly, VO(OPT) treatment (2.5 mg of vanadium per kg) significantly inhibited calpastatin and dystrophin breakdown (calpastatin: P<0.01 versus OVX-PO; dystrophin: P<0.05 versus OVX-PO; Figure 6A and 6B).
|
VO(OPT) Treatment Protects Against Isoproterenol-Induced Heart Failure
We recently found repeated β-adrenergic stimulation in OVX-PO female rats, dramatically increased in mortality rate.7 Kaplan-Meier survival plots are shown in Figure 7. Repeated treatment with isoproterenol (5 mg/kg for 28 days) had no effect on sham rats but markedly increased in mortality after OVX-PO treatment with a survival rate of 0% at 21 days. VO(OPT) treatment significantly reduced the mortality (P<0.01 versus OVX-PO, P<0.001 for 1.25 and 2.5 mg of vanadium; Figure 7). Taken together, reduced mortality by VO(OPT) treatment suggest that inhibition of decompensatory signaling pathways indeed protects the heart from the cardiac arrest under pathological conditions such as OVX-PO.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We defined here a novel cardioprotective mechanism of an organic vanadyl chelate, VO(OPT), through eNOS upregulation using PO-induced cardiac hypertrophy in OVX female rats. We documented previously that VO(OPT) elicits cardioprotective action through Akt activation using ischemia/reperfusion-induced heart injury in the rat.18 We recently introduced a novel heart injury model using OVX-PO female rats, which is attractive for testing cardioprotective drugs in hypertension-induced cardiac injury in postmenopausal women.7 The most striking phenomenon in the hearts of the OVX-PO female rats was impairment of Akt and eNOS signaling.7 Because VO(OPT) is a potent activator of phosphatidylinositol 3-kinase/Akt signaling through upregulation of tyrosine kinase receptor signaling,18,21 we speculated that VO(OPT) rescues the heart from hypertrophy-induced heart failure.
Like the single treatment,18 the continuous oral treatment with VO(OPT) for 14 days dose-dependently increased Akt activity. Akt can directly phosphorylate recombinant eNOS or eNOS in situ, at serine1177 (human)/1179 (bovine),16,30 thereby enhancing the eNOS activity. Interestingly, the continuous VO(OPT) treatment for 14 days not only increased Akt-mediated eNOS phosphorylation on Ser1179 but also enhanced eNOS protein expression at the high dose (2.50 mg of vanadium per kg). Localization and activity of eNOS are regulated by making a complex with a chaperone protein, HSP-90, and caveolin-3 in cardiomyocytes, especially in caveolae.30 We did not find any significant changes in HSP-90 in the OVX-PO group; thus, HSP-90 level is not the primary target for VO(OPT)-induced cardioprotection. Likewise, the caveolin-3 level was not affected by VO(OPT) treatment. Thus, eNOS phosphorylation is a predominant mechanism in VO(OPT)-induced cardioprotection. Because HSP-90 level tended to decrease after OVX-PO and increase by VO(OPT) treatment, more extensive studies are required to determine temporal changes and immunohistochemical localization of HSP-90 and eNOS after OVX-PO.
We also previously documented increased dystrophin breakdown after OVX-PO in female rats7 and after prolonged stimulation with endothelein-1 in cultured cardiomyocytes.31 The marked breakdown of dystrophin suggests involvement of calpain in OVX-PO–induced cardiac injury. We also found significant decrease in calpastatin levels after OVX-PO. Because VO(OPT) treatment significantly inhibited both calpastatin and dystrophin, break down was only by high dose of VO(OPT) (2.50 mg of vanadium per kg), suggesting that the inhibition of calpastatin and dystrophin breakdown is a consequence of the cardioprotection by VO(OPT).
Because overexpression of activated Akt in the heart in transgenic mice has been shown to promote cardiac hypertrophy and to protect cardiomyocytes from ischemia-reperfusion injury,32 Akt activation promotes cardiac hypertrophy through increased translation in the normal heart. However, we documented that Akt activation by VO(OPT) suppressed OVX-PO–induced hypertrophy in female rats. Lack of estrogen by OVX and PO leads to both reduction of eNOS expression and Akt phosphorylation. Under these conditions, Akt activation by VO(OPT) promotes cardiac remodeling to recover the physiological contraction and relaxation in the cardiomyocyte. Increased NO levels and decreased MLC phosphorylation partly account for this phenomenon. The inhibition of cardiac hypertrophy by OVX-PO was closely associated with recovery of HR, MABP, and contractile heart functions. The increased eNOS expression and/or phosphorylation likely mediate the recovery heart from OVX-PO–induced cardiac injury.
Finally, Kaplan-Meier survival data in our study clearly indicate that significantly increased mortality occurs only in the OVX-PO group after chronic β-adrenergic stimulation by isoproterenol (5 mg/kg).7 VO(OPT) treatment dose-dependently increased survival after acute cardiac stress caused by chronic β-adrenergic stimulation, suggesting that cardiac remodeling and recovered cardiac functions by VO(OPT) treatment contribute to the reduced mortality. This is a supportive observation of cardioprotective effects of VO(OPT) in the treatment of cardiac injury in postmenopausal women.
Previous study indicates that oral administration of VO(OPT) (10 mg of vanadium per kg) for 21 days has no effect on blood urea nitrogen and body weight in streptozotocin-induced diabetic rats.27 In the present series of experiments, none of the rats died in any of the studies conducted, and no gastrointestinal, hepatic, or renal toxicity was observed after 14 days of VO(OPT) treatment, as reported previously.27,28 Moreover, VO(OPT)-treated rats continue to gain weight throughout the experimental period, as reported previously.27,28,33 This suggests that the reduced weight gain caused by VO(OPT) administration is attributable to the reduced food and fluid intake.27,28,33
In conclusion, the most important observation presented here is that simultaneous severe reduction of eNOS and Akt activity in OVX-PO female rats likely triggers compensatory hypertrophy with increased heart contractility (Figure S6). Potentiation of the Akt and eNOS signaling pathways, along with inhibition of dystrophin breakdown, by treatment with VO(OPT) after OVX-PO likely contributes to increased survival after acute cardiac stress caused by chronic β-adrenergic stimulation (Figure S6). VO(OPT) likely accounts for the antihypertrophic effect and cardiac remodeling to rescue cardiomyocytes from heart failure through activation of Akt and eNOS signaling pathways.
Perspectives
We have reported previously that, in the PO-induced hypertrophy, the decreased eNOS and Akt activities are linked to functional impairment and adverse cardiac remodeling in OVX female rats.7 The present study revealed that the VO(OPT) treatment can attenuate the PO-induced cardiac hypertrophy through the activation of Akt and eNOS signaling pathways. Moreover, we have for the first time revealed that VO(OPT), one of the Akt activators,18,33 prevents cardiac hypertrophy and dysfunction in the pressure-overloaded OVX female rats and elucidates the possible intracellular mechanisms of the VO(OPT)-mediated cardioprotection against hypertrophic stimulation. These observations open a new therapeutic perspective for intervention in the hypertrophic process and, at the same time, modulation of the Akt pathway may provide novel therapeutic targets for which a new class of antihypertrophic drugs can be designed.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (19390150 to K.F.).
Disclosures
None.
Received June 17, 2008; first decision July 23, 2008; accepted October 29, 2008.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561–1566.[Abstract]
2. Luedde M, Katus HA, Frey N. Novel molecular targets in the treatment of cardiac hypertrophy. Recent Pat Cardiovasc Drug Discov. 2006; 1: 1–20.
3. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein-kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000; 6: 1004–1010.[CrossRef][Medline] [Order article via Infotrieve]
4. Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation. 2000; 101: 660–667.
5. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation. 2001; 104: 330–335.
6. Kemi OJ, Celi M, Wisloff U, Grimaldi S, Gallo P, Smith GL, Condorelli G, Ellingsen O. Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy. J Cell Physiol. 2008; 214: 316–321.[CrossRef][Medline] [Order article via Infotrieve]
7. Bhuiyan MS, Shioda N, Fukunaga K. Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats. Am J Physiol Endocrinol Metab. 2007; 293: E1606–E1614.
8. Sanada S, Node K, Minamino T, Takashima S, Ogai A, Asanuma H, Ogita H, Liao Y, Asakura M, Kim J, Hori M, Kitakaze M. Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats. Hypertension. 2003; 41: 963–967.
9. Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest. 1998; 101: 812–818.[Medline] [Order article via Infotrieve]
10. Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT, Lindsey ML, Vacon AC, Huang PL, Lee RT, Zapol WM, Picard MH. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation. 2001; 104: 1286–1291.
11. Linz W, Wohlfart P, Schölkens BA, Malinski T, Wiemer G. Interactions among ACE, kinins and NO. Cardiovasc Res. 1999; 43: 549–561.
12. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest. 2001; 108: 1429–1437.[CrossRef][Medline] [Order article via Infotrieve]
13. Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa S, Ide T, Wen J, Takeshita A. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002; 105: 868–873.
14. Ogita H, Node K, Liao Y, Ishikura F, Beppu S, Asanuma H, Sanada S, Takashima S, Minamino T, Hori M, Kitakaze M. Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice. Hypertension. 2004; 43: 237–242.
15. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature (Lond). 1999; 399: 601–605.[CrossRef][Medline] [Order article via Infotrieve]
16. Fulton D, Gratton J-P, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature (Lond). 1999; 399: 597–601.[CrossRef][Medline] [Order article via Infotrieve]
17. Takada Y, Hashimoto M, Kasahara J, Aihara K, Fukunaga K. Cytoprotective effect of sodium orthovanadate on ischemia/reperfusion-induced injury in rat Herat involves Akt activation and inhibition of fodrin breakdown and apoptosis. J Pharmacol Exp Ther. 2004; 311: 1249–1255.
18. Bhuiyan MS, Shibuya M, Shioda N, Moriguchi S, Kasahara J, Iwabuchi Y, Fukunaga K. Cytoprotective effect of bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) on myocardial ischemia/reperfusion injury elicits inhibition of Fas ligand and Bim expression and elevation of FLIP expression. Eur J Pharmacol. 2007; 571: 180–188.[Medline] [Order article via Infotrieve]
19. Bhuiyan MS, Takada Y, Shioda N, Moriguchi S, Kasahara J, Fukunaga K. Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovasc Ther. 2008; 26: 10–23.
20. Liem DA, Gho CC, Gho BC, Kazim S, Manintveld OC, Verdouw DD, Duncker DJ. The tyrosine phosphotase inhibitor bis(maltolato)oxovanadium (IV) attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels. J Pharmacol Exp Ther. 2004; 309: 1256–1262.
21. Shioda N, Ishigami T, Han F, Moriguchi S, Shibuya M, Iwabuchi Y, Fukunaga K. Activation of phophatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia. Neuroscience. 2007; 148: 221–229.[Medline] [Order article via Infotrieve]
22. Geraldes CF, Castro MM, Sherry AD, Ramasamy R. Influence of Vanadate on glycolysis, intracellular sodium and pH in perfused rat hearts. Mol Cell Biochem. 1997; 170: 53–63.[CrossRef][Medline] [Order article via Infotrieve]
23. Bhanot S, McNeill JH. Vanadyl sulfate lowers plasma insulin and blood pressure in spontaneously hypertensive rats. Hypertension. 1994; 24: 625–632.
24. Bhanot S, McNeill JH, Bryer-Ash M. Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats. Hypertension. 1994; 23: 308–312.
25. Bhanot S, Michoulas A, McNeill JH. Antihypertensive effects of vanadium compounds in hyperinsulinemic, hypertensive rats. Mol Cell Biochem. 1995; 153: 205–209.[CrossRef][Medline] [Order article via Infotrieve]
26. Sakurai H, Sano H, Takino T, Yasui H. An orally active antidiabetic vanadyl complex, bis(1-oxy-2-pyridinethiolato)oxovanadium (IV), with VO(S2O2) coordination mode; in vitro and in vivo evaluations in rats. J Inorg Biochem. 2000; 80: 99–105.[Medline] [Order article via Infotrieve]
27. Takeshita S, Kawamura I, Yasuno T, Kimura C, Yamamoto T, Seki J, Tamura A, Goto T. Amelioration of insulin resistance in diabetic ob/ob mice by a new type of rally active insulin-mimetic vanadyl complex: bis(1-oxy-2-pyridinethiolato)oxovanadium (IV), with VO(S2O2) coordination mode. J Inorg Biochem. 2001; 85: 179–186.[CrossRef][Medline] [Order article via Infotrieve]
28. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC, Bender JR. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3K-Akt pathway in human endothelial cells. Circ Res. 2000; 87: 677–682.
29. Zeng G, Nystrom Fh, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000; 101: 1539–1545.
30. Fulton D, Gratton J-P, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther. 2001; 299: 818–824.
31. Lu YM, Shioda N, Han F, Moriguchi S, Kasahara J, Shirasaki Y, Qin ZH, Fukunaga K. Imbalance between CaM kinase II and calcineurin activities impairs caffeine-induced calcium release in hypertrophic cardiomyocytes. Biochem Pharmacol. 2007; 74: 1727–1737.[CrossRef][Medline] [Order article via Infotrieve]
32. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A. 2002; 99: 12333–12338.
33. Bhuiyan MS, Shioda N, Fukunaga K. Targeting protein kinase B/Akt signaling with vanadium compounds for cardioprotection. Expert Opin Ther Targets. 2008; 12: 1217–1227.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||