Effect of Rosuvastatin on Cardiac Remodeling, Function, and Progression to Heart Failure in Hypertensive Heart With Established Left Ventricular Hypertrophy

Chang, Sung-A,Kim, Yong-Jin,Lee, Hye-Won,Kim, Dae-Hee,Kim, Hyung-Kwan,Chang, Hyuk-Jae,Sohn, Dae-Won,Oh, Byung-Hee,Park, Young-Bae Ovid Technologies Wolters Kluwer -American Heart A 2009 Hypertension Vol.54 No.3

<P>Hypertensive patients with left ventricular hypertrophy (LVH) are the most common high-risk group to develop heart failure with preserved ejection fraction. Recent reports have noted the favorable effect of statins on LVH. We evaluated the effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in a hypertensive rat model with established LVH. Dahl salt-sensitive rats were fed a high-salt diet until 13 weeks of age. After LVH was confirmed by echocardiography, rats were randomly assigned to control and statin treatment (n=18 each group). The statin-treated group was treated with rosuvastatin until 21 weeks of ages. Serial echocardiography, blood pressure monitoring, and miniaturized conductance catheter hemodynamic monitoring were performed at 21 weeks. Echocardiographic parameters were not significantly different between the groups. On hemodynamic monitoring, systolic performance parameters were similar between the groups, whereas end diastolic pressure-volume relationships were lower in the statin-treated group (0.014+/-0.008 versus 0.008+/-0.004 mm Hg/muL, P<0.05), suggesting improvement in myocardial stiffness. Pathological analysis showed attenuation of perivascular and interstitial fibrosis in the statin-treated group (P<0.02). Rosuvastatin therapy did not alleviate LVH in hypertensive rats with established LVH, but it attenuated myocardial fibrosis and LV stiffness. It seems that rosuvastatin has limited therapeutic value when used to prevent progression from LVH to heart failure in hypertensive hearts.</P>

Biology of Endoplasmic Reticulum Stress in the Heart

Groenendyk, Jody,Sreenivasaiah, Pradeep Kumar,Kim, Do Han,Agellon, Luis B.,Michalak, Marek Ovid Technologies Wolters Kluwer -American Heart A 2010 Circulation research Vol.107 No.10

<P>The endoplasmic reticulum (ER) is a multifunctional intracellular organelle supporting many processes required by virtually every mammalian cell, including cardiomyocytes. It performs diverse functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, posttranslational modification including N-linked glycosylation, and synthesis of phospholipids and steroids on the cytoplasmic side of the ER membrane, and regulation of Ca(2+) homeostasis. Perturbation of ER-associated functions results in ER stress via the activation of complex cytoplasmic and nuclear signaling pathways, collectively termed the unfolded protein response (UPR) (also known as misfolded protein response), leading to upregulation of expression of ER resident chaperones, inhibition of protein synthesis and activation of protein degradation. The UPR has been associated with numerous human pathologies, and it may play an important role in the pathophysiology of the heart. ER stress responses, ER Ca(2+) buffering, and protein and lipid turnover impact many cardiac functions, including energy metabolism, cardiogenesis, ischemic/reperfusion, cardiomyopathies, and heart failure. ER proteins and ER stress-associated pathways may play a role in the development of novel UPR-targeted therapies for cardiovascular diseases.</P>

The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload-Induced Cardiac Hypertrophy in Mice

Chiang, Chien-Sung,Huang, Ching-Hui,Chieng, Hockling,Chang, Ya-Ting,Chang, Dory,Chen, Ji-Jr,Chen, Yong-Cyuan,Chen, Yen-Hui,Shin, Hee-Sup,Campbell, Kevin P.,Chen, Chien-Chang Ovid Technologies Wolters Kluwer -American Heart A 2009 Circulation research Vol.104 No.4

<P>Voltage-gated T-type Ca(2+) channels (T-channels) are normally expressed during embryonic development in ventricular myocytes but are undetectable in adult ventricular myocytes. Interestingly, T-channels are reexpressed in hypertrophied or failing hearts. It is unclear whether T-channels play a role in the pathogenesis of cardiomyopathy and what the mechanism might be. Here we show that the alpha(1H) voltage-gated T-type Ca(2+) channel (Ca(v)3.2) is involved in the pathogenesis of cardiac hypertrophy via the activation of calcineurin/nuclear factor of activated T cells (NFAT) pathway. Specifically, pressure overload-induced hypertrophy was severely suppressed in mice deficient for Ca(v)3.2 (Ca(v)3.2(-/-)) but not in mice deficient for Ca(v)3.1 (Ca(v)3.1(-/-)). Angiotensin II-induced cardiac hypertrophy was also suppressed in Ca(v)3.2(-/-) mice. Consistent with these findings, cultured neonatal myocytes isolated from Ca(v)3.2(-/-) mice fail to respond hypertrophic stimulation by treatment with angiotensin II. Together, these results demonstrate the importance of Ca(v)3.2 in the development of cardiac hypertrophy both in vitro and in vivo. To test whether Ca(v)3.2 mediates the hypertrophic response through the calcineurin/NFAT pathway, we generated Ca(v)3.2(-/-), NFAT-luciferase reporter mice and showed that NFAT-luciferase reporter activity failed to increase after pressure overload in the Ca(v)3.2(-/-)/NFAT-Luc mice. Our results provide strong genetic evidence that Ca(v)3.2 indeed plays a pivotal role in the induction of calcineurin/NFAT hypertrophic signaling and is crucial for the activation of pathological cardiac hypertrophy.</P>

Cardiac Computed Tomographic Angiography for Detection of Cardiac Sources of Embolism in Stroke Patients

Hur, Jin,Kim, Young Jin,Lee, Hye-Jeong,Ha, Jong-Won,Heo, Ji Hoe,Choi, Eui-Young,Shim, Chi-Young,Kim, Tae Hoon,Nam, Ji Eun,Choe, Kyu Ok,Choi, Byoung Wook Ovid Technologies Wolters Kluwer -American Heart A 2009 Stroke Vol.40 No.6

<P>BACKGROUND AND PURPOSE: We assessed the diagnostic performance of 2-phase 64-slice cardiac computed tomographic angiography (CCTA) for the detection of a cardiac source of embolism in stroke patients using transesophageal echocardiography (TEE) as the reference standard. METHODS: We selected 137 patients who had experienced a recent episode of stroke and had undergone both 2-phase 64-slice CCTA and TEE within a period of 5 days. A potential cardiac source of embolism detected at both CCTA and TEE was recorded, and echocardiographic findings were categorized into high- and medium-risk sources based on the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. RESULTS: Of 137 patients, 100 abnormal findings in 91 patients were found on TEE, and 46 patients had no abnormal finding on TEE. The overall sensitivity, specificity, positive predictive value, and negative predictive value of the 64-slice CCTA for detecting cardiac sources of embolism were 89% (95% CI, 82%, 95%), 100% (95% CI, 90%, 100%), 100% (95% CI, 95%, 100%), and 81% (95% CI, 70%, 92%), respectively. TEE detected a total of 47 high-risk sources of embolism, whereas CT detected 44 lesions. For medium-risk sources of cardiac embolic stroke, TEE detected a total of 53 abnormal findings, whereas CT detected 44 abnormal findings. Of 53 lesions, there were 8 false-negative results on CT (5 patent foramen ovale and 3 atrial septal aneurysm). CONCLUSIONS: Two-phase 64-slice CCTA is a noninvasive and useful modality for detecting high-risk cardiac sources of embolism in stroke patients.</P>

Dual Angiogenic and Neurotrophic Effects of Bone Marrow-Derived Endothelial Progenitor Cells on Diabetic Neuropathy

Jeong, Jin-Ok,Kim, Mee-Ohk,Kim, Hyongbum,Lee, Min-Young,Kim, Sung-Whan,Ii, Masaaki,Lee, Jung-uek,Lee, Jiyoon,Choi, Yong Jin,Cho, Hyun-Jai,Lee, Namho,Silver, Marcy,Wecker, Andrea,Kim, Dong-Wook,Yoon, Y Ovid Technologies Wolters Kluwer -American Heart A 2009 CIRCULATION - Vol.119 No.5

<P>BACKGROUND: Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs. METHODS AND RESULTS: We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow-derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves. A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC-conditioned media. CONCLUSIONS: We demonstrate for the first time that bone marrow-derived EPCs could reverse various manifestations of diabetic neuropathy. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy.</P>

Hypertension Correlates With Lenticulostriate Arteries Visualized by 7T Magnetic Resonance Angiography

Kang, Chang-Ki,Park, Chan-A,Lee, Hyon,Kim, Sang-Hoon,Park, Cheol-Wan,Kim, Young-Bo,Cho, Zang-Hee Ovid Technologies Wolters Kluwer -American Heart A 2009 Hypertension Vol.54 No.5

<P>Hypertension, a major risk factor for stroke, is associated with altered arterial anatomy and function; however, the limited resolution of current imaging techniques has restricted the in vivo study of microvascular changes in the brain. In this report, we quantitatively examined the lenticulostriate arteries in hypertensive patients using ultrahigh-field 7T MRI. We compared the number of stems and branches, curvature, and tortuosity of the lenticulostriate arteries by 3D time-of-flight magnetic resonance angiography among 20 hypertensive patients (mean age: 46.6+/-9.1 years) and 20 age-matched healthy subjects (mean age: 47.7+/-8.1 years). The average numbers of stems and branches in hypertensive patients were significantly less than those of healthy subjects (P<0.002). However, this difference was abolished in older volunteers (>45 years old), whereas the difference between young hypertensive patients (< or = 45 years old) and age-matched healthy controls was augmented by 55% for stems and 91% for branches (P=0.001). In comparison, there were no differences in the average curvature and tortuosity of the lenticulostriate arteries and no significant difference when corrected for smoking (P=0.064). In conclusion, our results showed that there was a substantial difference in the lenticulostriate arteries of hypertensive patients compared with healthy individuals when observed in vivo by ultrahigh-resolution 7T magnetic resonance angiography, and the difference was considerable in young subjects.</P>

New Mechanism of Rosiglitazone to Reduce Neointimal Hyperplasia : Activation of Glycogen Synthase Kinase-3β Followed by Inhibition of MMP-9

Lee, Choon-Soo,Kwon, Yoo-Wook,Yang, Han-Mo,Kim, Sung-Hwan,Kim, Tae-Youn,Hur, Jin,Park, Kyung-Woo,Cho, Hyun-Jai,Kang, Hyun-Jae,Park, Young-Bae,Kim, Hyo-Soo Ovid Technologies Wolters Kluwer -American Heart A 2009 Arteriosclerosis, thrombosis, and vascular biology Vol.29 No.4

<P>Objective-Mechanism of neointimal hyperplasia after vascular injury includes activation of signaling pathways and matrix metalloproteinases (MMPs) that are involved in cell proliferation and migration. Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, was reported to inhibit neointimal hyperplasia in diabetic animals and humans. But the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone inhibited neointimal hyperplasia. Methods and Results-The proliferation and survival of cultured rat VSMCs were reduced by rosiglitazone, which was mediated by inhibition of ERK and activation GSK-3 beta, without change of Akt. The antiproliferative effect of rosiglitazone was reversed by GSK-3 beta inactivation. The migration of VSMCs was also suppressed by rosiglitazone that inhibited the expression and activity MMP-9 through GSK-3 beta activation. Thus migration of MMP-9(-/-) VSMCs from MMP-9 knockout mice was not affected by rosiglitazone. The underlying mechanism of MMP-9 suppression by rosiglitazone was that it inhibited NF-kappa B DNA binding activity, which was also dependent on GSK-3 beta. In rat carotid artery, balloon injury significantly inactivated GSK-3 beta with induction of MMP-9, which was effectively prevented by rosiglitazone. Thus, rosiglitazone significantly decreased the ratio of intima to media by reducing proliferation and inducing apoptosis of VSMCs at neointima, which was reversed by inactivation of GSK-3 beta with adenoviral transfer of catalytically-inactive GSK-KM gene. Conclusions-Rosiglitazone activates GSK-3 beta, which inhibits not only proliferation of VSMCs but also migration of VSMCs through blocking NF-kappa B-dependent MMP-9 activation. (Arterioscler Thromb Vasc Biol. 2009; 29: 472-479.)</P>

Angiopoietin-2 Exocytosis Is Stimulated by Sphingosine-1-Phosphate in Human Blood and Lymphatic Endothelial Cells

Jang, Cholsoon,Koh, Young Jun,Lim, Nam Kyu,Kang, Hyun Jung,Kim, Duk Hoon,Park, Sung Kwang,Lee, Gyun Min,Jeon, Choon Ju,Koh, Gou Young Ovid Technologies Wolters Kluwer -American Heart A 2009 Arteriosclerosis, thrombosis, and vascular biology Vol.29 No.3

<P>OBJECTIVE: Although diverse functions of angiopoietin-2 (Ang2) have been revealed, little is known about upstream signaling molecules regulating Ang2 exocytosis. We therefore investigated the mechanism of Ang2 exocytosis in human blood and lymphatic endothelial cells (BECs and LECs) by stimulation with sphingosine-1-phosphate (S1P). METHODS AND RESULTS: By immunostaining and ELISA analyses using our newly developed human Ang2-specific antibodies, Ang2 exocytosis from human endothelial cells was examined. Both exogenous and endogenous S1P trigger rapid Ang2 exocytosis in time- and dose-dependent manners. Intriguingly, S1P-induced Ang2 exocytosis is higher in LECs than BECs. These effects of S1P are mainly mediated by the endothelial differentiation gene receptor 1, which subsequently activates its downstream phospholipase C and intracellular calcium mobilization to trigger Ang2 exocytosis. Consistently, S1P also dramatically stimulates Ang2 exocytosis from the ECs of ex vivo-incubated blood vessels. CONCLUSION: These results imply that the rapid secretion of Ang2 by exocytosis from endothelial cells is another possible mechanism underlying S1P-induced angiogenesis and inflammation.</P>

Low Level of Low-Density Lipoprotein Cholesterol Increases Hemorrhagic Transformation in Large Artery Atherothrombosis but Not in Cardioembolism

Kim, Beom Joon,Lee, Seung-Hoon,Ryu, Wi-Sun,Kang, Bong Su,Kim, Chi Kyung,Yoon, Byung-Woo Ovid Technologies Wolters Kluwer -American Heart A 2009 Stroke Vol.40 No.5

<P>BACKGROUND AND PURPOSE: Low cholesterol level is known to be associated with increased cerebral hemorrhage. However, the associations of hemorrhagic transformation (HTf) after acute ischemic stroke and the low levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDLC) are largely undiscovered. METHODS: Of the 1034 patients with acute ischemic stroke who were consecutively admitted to our hospital, 377 patients with stroke attributable to large artery atherothrombosis (LAA; n=210) or cardioembolism (n=167) were selected for this study. Demographic and clinical information was collected and HTf was evaluated through follow-up T2*-weighted gradient-echo MRI performed usually within 1 week after stroke. Measurement of lipid parameters included TC, LDLC, high-density lipoprotein cholesterol, and triglyceride. RESULTS: Of the 377 patients, HTf was noted in 74 patients (19.6%). When patients were divided into 4 groups according to their TC and LDLC levels, the incidence of HTf was significantly elevated in the lowest quartile of each TC (P<0.01) and LDLC (P<0.01) level in LAA subgroup, but not in cardioembolism. After adjusting covariates, a low level of LDLC (OR, 0.46 per 1 mmol/L-increase; 95% CI, 0.22-0.98) was independently associated with HTf in LAA, but not in cardioembolism. There was no significant association between low levels of TC (OR, 0.63 per 1 mmol/L-increase; 95% CI, 0.35-1.15) and HTf in LAA. CONCLUSIONS: Low levels of LDLC, and possibly TC, are associated with greater risk of hemorrhagic transformation after acute ischemic stroke attributable to LAA.</P>

Cellular and Molecular Changes Associated With Inhibitory Effect of Pioglitazone on Neointimal Growth in Patients With Type 2 Diabetes After Zotarolimus-Eluting Stent Implantation

Hong, Soon Jun,Kim, Sung Tae,Kim, Tae-Jin,Kim, Eun-Ok,Ahn, Chul-Min,Park, Jae Hyoung,Kim, Je Sang,Lee, Kyung-Mi,Lim, Do-Sun Ovid Technologies Wolters Kluwer -American Heart A 2010 Arteriosclerosis, thrombosis, and vascular biology Vol.30 No.12