Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats

Jesmin, Subrina; Hattori, Yoshiyuki; Maeda, Seiji; Zaedi, Sohel; Sakuma, Ichiro; Miyauchi, Takashi

doi:10.1152/ajpheart.01142.2005

Cited by 17 publications

(7 citation statements)

References 60 publications

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“…This hypothesis is supported by a recent finding in diabetic rats which were normotensive. Calcium channel blocker benidipine normalized the endothelin system and reduced cardiac perivascular fibrosis (52), indicating that this effect is independent of the blood pressurelowering outcome. Second, it is not clarified in the current study whether IL-18 directly affects collagen synthesis or degradation, or both.…”

Section: Discussionmentioning

confidence: 92%

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

Shen

Tan

et al. 2008

Mol Med

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Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy, and elevated inflammatory status. To determine whether metabolic syndrome-associated elevation of the inflammatory cytokine interleukin-18 (IL-18) in serum and cardiac tissue, and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight, and blood insulin. Serum IL-18 levels in these rats were also elevated significantly. These changes were significantly different compared to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.

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Section: Discussionmentioning

confidence: 92%

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

Shen

Tan

et al. 2008

Mol Med

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“…Several animal models have been employed to gain more insight into the alterations in the ET system associated with diabetes (3,22,24). However, whereas many of these models exhibit other features of the metabolic syndrome in addition to diabetes (such as hyperlipidemia, obesity, or hypertension), the GK rat does not.…”

Section: Discussionmentioning

confidence: 99%

Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat

Matsumoto¹,

Ishida²,

Nakayama³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ET(A) and ET(B)) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32-38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ET(B) receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ET(A) antagonist) but not by BQ-788 (ET(B) antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by N(G)-nitro-l-arginine (l-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ET(A) and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ET(A), a defect in ET(B)-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.

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“…Likewise, in a model of ANG II-induced hypertrophy, mice deficient for ASK1-JNK signaling demonstrated an attenuation of cardiac fibrosis and remodeling (179). JNK activation downstream of ET-1 has also been implicated in perivascular remodeling in rat (183). Finally, matrix metalloproteinases (MMP) are well known to contribute to cardiac remodeling.…”

Section: Mitogen-activated Protein Kinases In Heart Function and mentioning

confidence: 99%

Mitogen-Activated Protein Kinase Signaling in the Heart: Angels Versus Demons in a Heart-Breaking Tale

Rose

Force²,

Wang³

2010

Physiological Reviews

632

582

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Among the myriad of intra-cellular signaling networks that govern the cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players that have been the focus of extensive investigations in the past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, and ERK5, are the targets of pharmacological and genetic manipulations to uncover their roles in cardiac development, function, and diseases. However, information reported in the literature from these efforts has not yet resulted in a clear view about the roles of specific MAPK pathways in heart. Rather, controversies from contradictive results have led to a perception that MAPKs are ambiguous characters in heart with both protective and detrimental effects. The primary object of this review is to provide a comprehensive overview of the current progress, in an effort to highlight the areas where consensus is established verses the ones where controversy remains. MAPKs in cardiac development, cardiac hypertrophy, ischemia/reperfusion injury, and pathological remodeling are the main focuses of this review as these represent the most critical issues for evaluating MAPKs as viable targets of therapeutic development. The studies presented in this review will help to reveal the major challenges in the field and the limitations of current approaches and point to a critical need in future studies to gain better understanding of the fundamental mechanisms of MAPK function and regulation in the heart.

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Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats

Abstract: dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats.

Cited by 17 publications

References 60 publications

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat

Mitogen-Activated Protein Kinase Signaling in the Heart: Angels Versus Demons in a Heart-Breaking Tale

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