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Lin Xu,
Xu-Yong Li,
Yu Liu, Hai-Tao Li,
Jing Chen,
Xiao-Yan Li,
Xue-Jun Jiang,
Gang Wu,
Yan-Hong Tang,
Xi Wang,
Cong-Xin Huang
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ABSTRACT: L-type calcium current (I(Ca)) plays a critical role in excitation-contraction coupling (ECC). Unlike transient outward K(+) current (I(to)), it is controversial whether I(Ca) transmural gradient exists in left ventricle. Although previous studies have shown some evidences for I(Ca) heterogeneity, the mechanism is still unknown. In this study, the authors recorded I(Ca) from epicardial (EPI) and endocardial (ENDO) myocytes isolated from murine left ventricle using patch-clamp technique. It was found that I(Ca) density was obviously larger in EPI than in ENDO (7.3 ± 0.3 pA/pF vs. 6.2 ± 0.2 pA/pF, at test potential of +10 mV, P < 0.05). The characteristics of I(Ca) showed no difference between these two regions except for the fast inactivation time constants (9.9 ± 0.9 ms in EPI vs. 13.5 ± 0.9 ms in ENDO, at test potential of +10 mV, P < 0.05). In addition, it was explored the molecular mechanism underlying I(Ca) transmural gradient by Western blot. The authors demonstrated that a higher activity of CaMKII in ENDO cells induced more nuclear translocation of p65, a component of nuclear factor-kappa B (NF-kB). Consequently, p65 in ENDO inhibited more transcription of Cav1.2, the main encoding gene for L-type calcium channels (LTCCs). These results reveal a difference in CaMKII/p65 signal pathway between EPI and ENDO that underlies this mechanism of I(Ca) heterogeneity in murine left ventricle.
Molecular and Cellular Biochemistry 03/2011; 352(1-2):239-46. · 2.06 Impact Factor
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ABSTRACT: To investigate the effects of NADPH oxidase inhibition on cardiac function and myocardial calcium regulatory proteins mRNA expressions in rabbits with heart failure (HF).
HF was induced by experimental aortic insufficiency and abdominal aortic constriction, HF animals were treated with oral apocynin (15 mg/d), a NADPH oxidase inhibitor or equal dose placebo. Eight weeks later, cardiac function was measured by echocardiography. Myocardial NADPH oxidase activity was evaluated by NADPH dependent superoxide production examined using superoxide dismutase-inhibitable cytochrome c reduction. Sarcoplasmic reticulum Ca(2+)ATPase (SERCA2a), ryanodine receptor 2 (RyR2), phospholamban (PLB) and sodium-calcium exchanger (NCX) were determined by RT-PCR.
Rabbits with HF developed ventricular dilatation and cardiac dysfunction, as well as increase in myocardial NADPH oxidase activity, decreases in mRNA expression of SERCA2a, RyR2 and PLB, and increase in mRNA expression of NCX. Apocynin significantly reduced NADPH oxidase activity (P < 0.05), upregulated SERCA2a, RyR2 and PLB mRNA expressions (SERCA2a/GAPDH: 0.63 +/- 0.11 vs. 0.34 +/- 0.08, RyR2/GAPDH: 0.23 +/- 0.04 vs. 0.17 +/- 0.06, PLB/GAPDH:1.28 +/- 0.13 vs. 0.95 +/- 0.09, P < 0.05), downregulated NCX mRNA expression (NCX/GAPDH: 0.67 +/- 0.10 vs. 0.95 +/- 0.12, P < 0.05), and improved cardiac function [LVEF: (60.06 +/- 10.07)% vs. (38.87 +/- 3.31)%, LVFS: (30.12 +/- 6.56)% vs. (17.40 +/- 2.45)%, P < 0.05] in rabbits with HF.
NADPH oxidase inhibition improves cardiac function possibly by preventing abnormal alterations in myocardial calcium regulatory proteins in failing heart.
Zhonghua xin xue guan bing za zhi [Chinese journal of cardiovascular diseases] 10/2009; 37(10):883-6.
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ABSTRACT: Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial cardiac effects on chronic heart failure (CHF) recently. In this study, we attempted to investigate the mechanisms for the effect of ghrelin on ventricular remodeling following acute myocardial infarction (MI). Ligation of a coronary artery was used to create an MI in rats. One week after MI, ghrelin (100 microg/kg) or saline was injected subcutaneously twice a day for 4 weeks. When compared to sham groups, ghrelin administration significantly decreased left ventricular (LV) remodeling in post-MI rats, as indicated by increased LV maximum rate of pressure, LV fractional shortening and scar thickness; and decreased LV end-diastolic pressure, LV end-systolic diameter, LV end-diastolic diameter and cardiocytocytes apoptosis. Moreover, ghrelin inhibited the inflammatory response, as shown by decreased mRNA and protein levels of interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha). Subsequently, the expression of matrix metalloproteinase (MMP)-2 and MMP-9 were also inhibited by ghrelin injection. Ghrelin alleviates LV dysfunction and ventricular remodeling in post-MI rats. This suggests that the beneficial effects of ghrelin on CHF may result from an inhibition of the inflammatory response.
Peptides 09/2009; 30(12):2286-91. · 2.43 Impact Factor
