Ming-Ming Ma

Sun Yat-Sen University, Shengcheng, Guangdong, China

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Publications (9)39.41 Total impact

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    ABSTRACT: Aims: Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling. Methods and results: By integrating quantitative PCR, western blotting, patch clamping, and Ca(2+) imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats. Importantly, administration of pyrazole 3 (Pyr3), a TRPC3 channel blocker, attenuated cerebrovascular remodelling. During hypertension, epidermal growth factor receptor (EGFR) was transactivated, as evidenced by marked EGFR phosphorylation, increased pro-HB-EGF shedding, and elevated activity of ADAM17 (HB-EGF sheddase). ADAM17 activity was increased owing to enhanced activation rather than elevated expression. Remarkably, Pyr3 treatment suppressed EGFR transactivation in hypertension. In proliferating basilar artery smooth muscle cells or basilar arteries of hypertensive rats, co-immunoprecipitation assay revealed an interaction between TRPC3 and ADAM17 upon Ang II stimulation. Conclusion: Collectively, we demonstrated that enhanced EGFR transactivation, due to increased TRPC3 expression and functional coupling of TRPC3/ADAM17, resulted in cerebrovascular remodelling. Therefore, TRPC3-induced EGFR transactivation may be therapeutically exploited to prevent hypertension-induced cerebrovascular remodelling.
    Cardiovascular Research 11/2015; DOI:10.1093/cvr/cvv246 · 5.94 Impact Factor
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    ABSTRACT: Background and purpose: Angiotensin II (AngII) induces vascular smooth muscle cell (VSMC) migration and growth, which is responsible for vascular remodeling in some cardiovascular diseases. It has been demonstrated to activate a Cl(-) current, but the underlying mechanism is not clear. Experimental approach: Whole-cell patch clamp, co-immunoprecipitation (co-IP), site-specific mutagenesis, angiotensin II-induced hypertensive mice model were used. Key results: In VSMC, AngII induced a ClC-3-dependent Cl(-) current that was abolished in ClC-3 null mice. The activation mechanism of this AngII-induced Cl(-) current was related to the interaction between ClC-3 and Rho-kinase 2 (ROCK2), as shown by N-terminal or C-terminal truncation of ClC-3, ROCK2 siRNA and Co-IP experiments. We then tried to establish whether or not the phosphorylation site of ClC-3 at threonine 532 is critical for AngII-induced Cl(-) current and VSMC migration through ROCK. The ClC-3 T532D mutant (mutation of threonine 532 to aspartate), mimicking the phosphorylation state of ClC-3, significantly potentiated AngII-induced Cl(-) current and VSMC migration; while ClC-3 T532A (mutation of threonine 532 to alanine) had the opposite effects. Furthermore, we found a marked decrease in AngII-induced VSMC migration in ClC-3 null mice that was insensitive to Y27632, an inhibitor of ROCK2. In addition, AngII-induced cerebrovascular remodeling was ameliorated in ClC-3 null mice, possibly by ROCK2 pathway. Conclusions and implications: ClC-3 protein phosphorylation at threonine 532 by ROCK2 is required for AngII-induced Cl(-) current and VSMC migration that are involved in AngII-induced hypertensive vascular remodeling.
    British Journal of Pharmacology 11/2015; DOI:10.1111/bph.13385 · 4.84 Impact Factor
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    ABSTRACT: Background: Recent evidence suggested that ClC-3, encoding Cl(-) channel or Cl(-)/H(+) antiporter, plays a critical role in regulation of a variety of physiological functions. However, remarkably little is known about whether ClC-3 is involved in atherosclerosis. This study aims to establish the involvement and direct role of ClC-3 in atherogenesis and underlying mechanisms by using ClC-3 and ApoE double null mice. Methods and results: After a 16-week western-type high-fat diet, the ClC-3(+/+) ApoE(-/-) mice developed widespread atherosclerotic lesions in aorta. However, the lesion size was significantly reduced in aorta of ClC-3(-/-)ApoE(-/-) mice. Compared with the ClC-3(+/+) controls, there was significantly decreased ox-LDL binding and uptake in isolated peritoneal macrophages from ClC-3(-/-) mice. Moreover, the expression of scavenger receptor SR-A, but not CD36, was significantly decreased in both ClC-3(-/-) peritoneal macrophages and aortic lesions from ClC-3(-/-)ApoE(-/-) mice. These findings were further confirmed in ox-LDL-treated RAW264.7 macrophages, which showed that silence of ClC-3 inhibited SR-A expression, ox-LDL accumulation and foam cell formation, whereas overexpression of ClC-3 produced the opposite effects. In addition, ClC-3 siRNA significantly inhibited, whereas ClC-3 overexpression increased, the phosphorylation of JNK/p38 MAPK in ox-LDL-treated RAW264.7 foam cells. Pretreatment with JNK or p38 inhibitor abolished ClC-3-induced increase in SR-A expression and ox-LDL uptake. Finally, the increased JNK/p38 phosphorylation and SR-A expression induced by ClC-3 could be mimicked by reduction of [Cl(-)]i by low Cl(-) solution. Conclusions: Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation.
    Journal of Molecular and Cellular Cardiology 09/2015; 87. DOI:10.1016/j.yjmcc.2015.09.002 · 4.66 Impact Factor
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    ABSTRACT: Cystic fibrosis transmembrane conductance regulator (CFTR) acts as a cAMP-dependent chloride channel, has been studied in various types of cells. CFTR is abundantly expressed in vascular smooth muscle cells and closely linked to vascular tone regulation. However, the functional significance of CFTR in basilar vascular smooth muscle cells (BASMCs) remains elusive. Accumulating evidence has shown the direct role of CFTR in cell apoptosis that contributes to several main pathological events in CF, such as inflammation, lung injury and pancreatic insufficiency. We therefore investigated the role of CFTR in BASMC apoptotic process induced by hydrogen peroxide (H2O2). We found that H2O2-induced cell apoptosis was parallel to a significant decrease in endogenous CFTR protein expression. Silencing CFTR with adenovirus-mediated CFTR specific siRNA further enhanced H2O2-induced BASMC injury, mitochondrial cytochrome c release into cytoplasm, cleaved caspase-3 and -9 protein expression and oxidized glutathione levels; while decreased cell viability, the Bcl-2/Bax ratio, mitochondrial membrane potential, total glutathione levels, activities of superoxide dismutase and catalase. The pharmacological activation of CFTR with forskolin produced the opposite effects. These results strongly suggest that CFTR may modulate oxidative stress-related BASMC apoptosis through the cAMP- and mitochondria-dependent pathway and regulating endogenous antioxidant defense system.
    APOPTOSIS 07/2014; 19(9). DOI:10.1007/s10495-014-1014-z · 3.69 Impact Factor
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    ABSTRACT: Cerebrovascular remodeling is one of important risk factors of stroke. The underlying mechanisms are unclear. Integrin β3 and volume regulated ClC-3 Cl(-) channels have recently been implicated as important contributors to vascular cell proliferation. Therefore, we investigated the role of integrin β3 in cerebrovascular remodeling and related Cl(-) signalling pathway. Cl(-) currents were recorded using patch clamp technique. The expression of integrin β3 in hypertensive animals was examined by western blot and immunohistochemisty. Immunoprecipitation, cDNA and siRNA transfection were employed to investigate the integrin β3/Src/ClC-3 signalling. The expression of integrin β3 was up-regulated in stroke-prone spontaneously hypertensive rats, 2-kidney 2-clip hypertensive rats and angiotensin II-infused hypertensive mice. Integrin β3 expression was positively correlated with medial cross-sectional area and ClC-3 expression in basilar artery of 2-kidney 2-clip hypertensive rats. Knockdown of integrin β3 inhibited rat basilar vascular smooth muscle cell proliferation induced by angiotensin II. Co-immunoprecipitation and immunofluorescence experiments revealed a physical interaction between integrin β3, Src and ClC-3 protein. The integrin β3/Src/ClC-3 signalling were involved both in hypoosmotic stress and angiotensin II- induced volume regulated chloride channel activation. Tyrosine 284 within a concensus Src-phosphorylation site was the key point for ClC-3 channel activation. ClC-3 knockout significantly attenuated angiotensin II-induced cerebrovascular remodeling. Integrin β3 mediated cerebrovascular remodeling during hypertension via Src/ClC-3 signalling pathway.
    British Journal of Pharmacology 02/2014; 171(13). DOI:10.1111/bph.12654 · 4.84 Impact Factor
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    ABSTRACT: We have previously demonstrated that ClC-3 chloride channel activity and expression are significantly increased in remodeled cerebral vessels of hypertensive rats. This study aims to examine whether this channel directly regulates cerebrovascular remodeling during hypertension by using ClC-3(-/-) mice.Methods and ResultsAfter DOCA-salt treatment, medial cross-sectional area, media thickness, and media-lumen ratio of the basilar artery of ClC-3(+/+) mice were significantly increased, accompanied by reduced lumen diameter, indicating apparent vascular remodeling. The vascular ultrastructure of ClC-3(+/+) hypertensive mice by electron microscopy revealed obvious disarray of SMCs and extracellular matrix accumulation. Immunofluorescence analysis showed that fibronectin was overexpressed in ClC-3(+/+) DOCA-salt mice. All of these vascular structure alterations were prevented in ClC-3(-/-) mice despite DOCA-salt treatment. However, propranolol, which reduced blood pressure as effectively as ClC-3 deficiency, failed to prevent basilar artery from remodeling. The vascular structure injury in ClC-3(+/+) hypertensive mice was accompanied by significantly increased expression of matrix metalloproteinase (MMP)-2, membrane-type (MT)1-MMP and tissue inhibitor of metalloproteinase (TIMP)-2, which was inhibited by ClC-3 knockout. Additionally, the increase in transforming growth factor (TGF)-β1 level in serum, as well as phosphorylation of Smad3 at serine 423/425 in basilar artery, induced by DOCA-salt, was markedly prevented in ClC-3(-/-) mice. Our findings suggest that ClC-3 deficiency attenuates cerebrovascular remodeling possibly via suppression of MMPs/TIMP expression and TGF-β1/Smad3 signaling pathway in this hypertension.
    Cardiovascular Research 06/2013; 100(1). DOI:10.1093/cvr/cvt156 · 5.94 Impact Factor
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    ABSTRACT: AimsThe ClC-3 chloride channel (and current, ICl,ClC-3) plays an important role in cell volume regulation, proliferation, and apoptosis in vascular smooth muscle cells, and is a potential target for prevention of vascular remodelling and stroke. However, modulation of ICl,ClC-3 by intercellular signalling is not fully understood. Although it has been suggested that tyrosine phosphorylation is required for ICl,ClC-3 activation, the potential tyrosine residues in the ClC-3 protein are not clear. In the present study, the critical tyrosine residues in ClC-3 protein were investigated.Methods and resultsSite-specific mutagenesis, immunoprecipitation, patch clamp, and Cl- transport imaging techniques were employed. We found that activation of ICl,ClC-3 was associated with tyrosine phosphorylation of the ClC-3 protein. Three potential tyrosine residues, Y284, Y572, and Y631, were mutated to phenylalanine, and only mutation, at Y284 within a consensus Src-phosphorylation site, completely blocked ICl,ClC-3. Phosphomimetic mutation Y284D increased the Cl- current and Cl - efflux mediated by ClC-3. The Y284F mutation completely abolished the protective effect of ClC-3 on apoptosis, whereas the Y284D mutation potentiated it. There was an interaction between Src kinase and ClC-3 protein, and the Y284D mutation abrogated the inhibitory effect of SU6656, a Src family kinase inhibitor, on ClC-3 Cl- current.Conclusion Tyrosine 284 phosphorylation in the ClC-3 channel targeted by Src kinase is an important molecular mechanism for ClC-3 channel activation. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved.
    Cardiovascular Research 03/2013; 98(3). DOI:10.1093/cvr/cvt063 · 5.94 Impact Factor
  • Lei Jiang · Yun Liu · Ming-Ming Ma · Yong-Bo Tang · Jia-Guo Zhou · Yong-Yuan Guan ·
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    ABSTRACT: Bestrophin 3 (Best-3) is expressed in a variety of tissues, such as cardiac, smooth muscle and renal tissues, and it is highly expressed in rat basilar arterial smooth muscle cells (BASMCs). Lee et al. (Biochim Biophys Acta 1823:1864-1876, 2012) reported that Best-3 prevented apoptotic cell death induced by endoplasmic reticulum stress. In the present study, we used small interference RNA (siRNA) and bestrophin 3 cDNA transfection strategy to investigate whether Best-3 can provide a protective effect on apoptosis induced by hydrogen peroxide (H2O2) in BASMCs and studied the underlying mechanisms. We found that silencing of Best-3 with siRNA resulted in an increased H2O2-induced apoptosis and a decreased cell viability, whereas overexpression of Best-3 significantly prevented the apoptotic cell death and increased the cell viability. Overexpression of Best-3 could stabilize the mitochondrial membrane potential, increase the ratio of Bcl-2/Bax, and decrease cytochrome c release and caspase-3 activation. In contrast, silencing of Best-3 produced the opposite effects. Our present data strongly suggest that Best-3 inhibits apoptosis induced by H2O2 in BASMCs through mitochondria dependent pathway.
    Apoptosis 03/2013; 18(5). DOI:10.1007/s10495-013-0828-4 · 3.69 Impact Factor
  • Ming-Ming Ma · Shi-Yang Li · Mi Wang · Yong-Yuan Guan ·
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    ABSTRACT: The cerebrovascular remodeling is a prominent feature of hypertension and considered as a major risk of stroke. Statins may suppress the activation of the Rho/Rho-kinase pathway and have pleiotropic actions against the development of vascular remodeling. We hypothesized that the inhibition of the Rho/Rho-kinase pathway by simvastatin during hypertension could recuperate the pathological changes of basilar artery through the downregulation of cell proliferation. To resolve the problem, we used 2-kid, 2-clip rat as a hypertension model and evaluated the effect of simvastatin on the Rho/Rho-kinase pathway. In addition, we assessed the changes of the proliferation rate by CCK-8 assay in basilar artery smooth muscle cells. Our results from this study showed that a continuous increase in the plasma endothelin-1 (ET-1) concentration and the Rho/Rho-kinase activity was positively correlated with changes in blood pressure in the hypertensive rat. Simvastatin ameliorated the upregulated Rho/Rho-kinase activity and cell proliferation during hypertension. Moreover, simvastatin, the RhoA inhibitor C3, and the RhoA-kinase inhibitor Y27632 all attenuated the proliferation rate induced by ET-1 in basilar artery smooth muscle cells via the Rho/Rho-kinase signaling pathway. In conclusion, simvastatin attenuated ET-1-induced proliferation through the Rho/Rho-kinase signaling pathway in hypertensive rat basilar artery, and it may be an excellent reagent to protect vascular remodeling and stroke.
    Journal of cardiovascular pharmacology 03/2012; 59(6):576-82. DOI:10.1097/FJC.0b013e318250ba2c · 2.14 Impact Factor
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    ABSTRACT: Our previous studies showed that ginsenoside-Rd, a purified component from Panax notoginseng, inhibited cell proliferation and reversed basilar artery remodeling. The aim of this study was to investigate whether ginsenoside- Rd influences H(2)O(2)-induced apoptosis in basilar artery smooth muscle cells (BASMCs). The results showed that ginsenoside-Rd significantly potentiated H(2)O(2)-induced cell death and cell apoptosis. This resulted in a concentration-dependent reduction of the cell viability. Ginsenoside-Rd further increased cytochrome C release and caspase-9/caspase-3 activations, and reduced the stability of mitochondrial membrane potential (MMP) and the ratio of Bcl-2/Bax. Cyclosporine A, an inhibitor of mitochondrial-permeability transition, inhibited alteration of mitochondrial permeability induced by H(2)O(2) and reversed the effect of ginsenoside-Rd on MMP. Our data strongly suggest that ginsenoside-Rd potentiated H(2)O(2)-induced apoptosis of BASMCs through the mitochondria-dependent pathway.
    Apoptosis 11/2011; 17(2):113-20. DOI:10.1007/s10495-011-0671-4 · 3.69 Impact Factor