Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/ Rac-1 activity
Seojin Kang
1
College of Pharmacy, Seoul National University, Seoul, Korea
,
Keunyoung Kim
1
College of Pharmacy, Seoul National University, Seoul, Korea
,
Ji-Yoon Noh
1
College of Pharmacy, Seoul National University, Seoul, Korea
,
Yeryeon Jung
1
College of Pharmacy, Seoul National University, Seoul, Korea
,
Ok-Nam Bae
2
College of Pharmacy, Hanyang University, Ansan, Korea
,
Kyung-Min Lim
3
College of Pharmacy, Ewha Womans University, Seoul, Korea
,
Jin-Ho Chung
1
College of Pharmacy, Seoul National University, Seoul, Korea
› Author AffiliationsFinancial support: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP) (2012R1A2A2A01011705).
Statins, lipid-lowering agents for the prevention of atherosclerosis and fatal coronary heart diseases, have pleiotropic modalities on the function and physiology of vascular smooth muscle that include anti-contractile and pro-apoptotic effects. These effects were suggested to stem from the inhibition of small GTPase Rho A, but they are largely regarded as distinct and unrelated. Recently, we discovered that simvastatin causes both contractile dysfunction and apoptosis of vascular smooth muscle cells (VSMCs), reflecting that they may be closely related, yet their connecting link remains unexplained. Here, we elaborated the mechanism underlying simvastatin-induced apoptosis of normal VSMCs in connection with contractile dysfunction. Repeated oral administration of simvastatin to rats in vivo resulted in contractile dysfunction and apoptosis of vascular smooth muscle, of which pattern was well reproduced in rat VSMCs in vitro. Of note, contractile dysfunction and apoptosis occurred in concerted manners both in vivo and in vitro in the aspects of time course and dose of exposure. In rat VSMCs, simvastatin impaired the activation of small GTPases, RhoA along with Rac-1, which resulted in the disruption of actin integrity, a pivotal factor both for the generation of contractile force and survival of VSMCs. In line with the disruption of actin integrity, Bmf, a pro-apoptotic factor bound to intact actin, dissociated and translocated into mitochondria, which corresponded well with the dissipation of mitochondrial membrane potential, caspase-3 activation and ultimately apoptosis. These events were all rescued by an actin stabilisation agent, jasplakinolide as well as geranylgeraniol, indicating that damages of the actin integrity from disrupted activation of RhoA/ Rac-1 lies at the center of simvastatin-induced contractile dysfunction and apoptosis in vascular smooth muscle.
Supplementary Material to this article is available online at www.thrombosis-online.com.
1
Nissen SE,
Tuzcu EM,
Schoenhagen P.
et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352: 29-38.
5
Sauzeau V,
Le Jeune H,
Cario-Toumaniantz C.
et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitisation of contraction in vascular smooth muscle. J Biol Chem 2000; 275: 21722-21729.
6
Seko T,
Ito M,
Kureishi Y.
et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res 2003; 92: 411-418.
7
Sauzeau V,
Le Mellionnec E,
Bertoglio J.
et al. Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res 2001; 88: 1102-1104.
10
Guijarro C,
Blanco-Colio LM,
Ortego M.
et al. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 1998; 83: 490-500.
12
De Pinieux G,
Chariot P,
Ammi-Said M.
et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996; 42: 333-337.
21
Puthalakath H,
Villunger A,
O’Reilly LA.
et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001; 293: 1829-1832.
22
Aoki T,
Nishimura H,
Nakagawa S.
et al. Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Arzneimittelforschung 1997; 47: 904-909.
23
Xu QY,
Liu YH,
Zhang Q.
et al. Metabolomic analysis of simvastatin and fenofibrate intervention in high-lipid diet-induced hyperlipidemia rats. Acta Pharmacol Sin 2014; 35: 1265-1273.
25
Varkuti BH,
Yang Z,
Kintses B.
et al. A novel actin binding site of myosin required for effective muscle contraction. Nat Struct Mol Biol 2012; 19: 299-306.
27
Rubtsova SN,
Kondratov RV,
Kopnin PB.
et al. Disruption of actin microfilaments by cytochalasin D leads to activation of p53. FEBS Lett 1998; 430: 353-357.
28
Konishi H,
Kikuchi S,
Ochiai T.
et al. Latrunculin a has a strong anticancer effect in a peritoneal dissemination model of human gastric cancer in mice. Anticancer Res 2009; 29: 2091-2097.
29
Anderl J,
Echner H,
Faulstich H..
Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology. Beilstein J Org Chem 2012; 8: 2072-2084.
30
Leeper NJ,
Raiesdana A,
Kojima Y.
et al. Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler Thromb Vasc Biol 2013; 33: e1-e10.
31
Guijarro C,
Blanco-Colio LM,
Ortego M.
et al. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 1998; 83: 490-500.
32
Min J,
Reznichenko M,
Poythress RH.
et al. Src modulates contractile vascular smooth muscle function via regulation of focal adhesions. J Cell Physiol 2012; 227: 3585-3592.
33
Wall BT,
Dirks ML,
van Loon LJ..
Skeletal muscle atrophy during short-term disuse: implications for age-related sarcopenia. Age Res Rev 2013; 12: 898-906.
36
Zhu S,
Nagashima M,
Khan MA.
et al. Lack of caspase-3 attenuates immobilisation-induced muscle atrophy and loss of tension generation along with mitigation of apoptosis and inflammation. Muscle Nerve 2013; 47: 711-721.
38
VanBrocklin MW,
Verhaegen M,
Soengas MS.
et al. Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res 2009; 69: 1985-1994.
39
Kutuk O,
Letai A..
Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells. Cell Death Differ 2010; 17: 1624-1635.
