Effects of Atorvastatin on Angiogenesis in Hindlimb Ischemia and Endothelial Progenitor Cell Formation in Rats

Matsumura, Masanori; Fukuda, Noboru; Kobayashi, Noboru; Umezawa, Hisaki; Takasaka, Ayako; Matsumoto, Tarô; Yao, En-Hui; Ueno, Takayoshi; Negishi, Nanao

doi:10.5551/jat.no026

Cited by 50 publications

(36 citation statements)

References 34 publications

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“…We further investigated the cardio-protective mechanism of CORM-3 focusing on the mobilization of endothelial progenitor cells (EPCs) from bone marrow to the myocardial tissue, the ultimate goal being the repair of injured tissues. In this case, we measured the cardiac expressions of CD117/c-kit, marker of bone marrowderived EPCs, and CD34, marker of endothelial progenitor cells with the capacity to induce angiogenesis (Matsumura et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

Filippo

Perretti

Rossi

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Here, we have studied the effects of a carbon monoxide-releasing molecule (CORM-3, tricarbonylchloro(glycinato)ruthenium(II)) on acute myocardial ischemia/reperfusion (I/R) injury in hyperglycaemic streptozotocin-treated rats (STZ rats). Occlusion of the left descending coronary artery for 25 min followed by a 2-h reperfusion in STZ-induced hyperglycaemic rats was used as the model. CORM-3 and its inactive counterpart (iCORM-3) were administered 1 h prior to ischemia. The parameters measured included myocardial infarct size (IS) and a selection of inflammatory, oxidative markers and endothelial progenitor cells (CD34⁺ and CD117/c-kit⁺. In STZ-induced hyperglycaemic rats, occlusion of the left descending coronary artery caused injury of the myocardial tissue with an IS of ~70%, expressed as fraction of the area at risk. Given intraperitoneally 1 h prior to ischemia, CORM-3 (2-8 mg/kg) afforded significant dose-dependent cardio-protection. Specifically, pre-treatment with CORM-3 reduced infarct size by 14 ± 0.6%, 34 ± 1% and 53 ± 1.6% for doses of 2, 4 and 8 mg/kg, respectively. A negative control (iCORM-3) failed to prevent the cardiac damage induced by I/R. CORM-3 pre-treatment augmented cardiac heme oxygenase-1 (HO-1) protein levels and was associated with an increased number of CD34⁺- and CD117/c-kit⁺-positive immunostaining. Modulation of these markers was associated with augmented cardiac eNOS expression and levels of the cytokines TNF-α and IL-1 beta. CORM-3 afforded significant cardio-protection against acute myocardial infarction in STZ-induced hyperglycaemic rats through liberation of small amounts of CO. Of interest, CORM-3 promoted recruitment of the endogenous endothelial progenitor cells within the myocardium, possibly through modulation of cardiac HO-1 and eNOS expression and/or function.

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Section: Introductionmentioning

confidence: 99%

Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

Filippo

Perretti

Rossi

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Additionally, increased capillary formation and neuroblast migration activity occurred, which could be abolished by inhibition of ANG1. Such indirect pro-angiogenic effects could also be demonstrated for other HMG-CoA reductase inhibitors [107].…”

Section: Indirect Modulation Of the Ang/tie Axismentioning

confidence: 79%

The angiopoietin/TIE receptor system: Focusing its role for ischemia-reperfusion injury

Hilbert

Klaschik

2015

Cytokine & Growth Factor Reviews

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“…We recently demonstrated that atorvastatin induces proangiogenic effects, with increase in the expression of angiogenic factors, including vascular endothelial growth factor, interluekin-8, angiopoietins and eNOS, in the ischemic hindlimbs of rats. 19 Statins have been reported to increase HO-1 production and, thus, inhibit oxidation in vivo. 12 Hsu et al 20 demonstrated that oral administration of statins increases HO-1 production in the mouse liver, lung, brain and heart, and suggested that the antioxidative effects of statins in cardiovascular tissues are strongly induced by HO-1.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we demonstrated that a statin strongly potentiates colony formation among endothelial progenitor cells during angiogenesis and repairs the endothelium in oxidative hypertensive rats with increases in HO-1 in vivo. 19 It is possible that the proangiogenic effects of simvastatin also protected against cardiac fibrosis. Suzuki et al 21 recently demonstrated that pravastatin mobilizes bone marrow progenitor cells in hibernating hearts and increases the number of myocytes that reenter the growth and mitotic phases of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading

et al. 2010

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Statins exert pleiotropic effects, including antioxidative and cellular protective effects. Endogenous adrenomedullin (AM) induces anti-inflammatory, anti-fibrotic and proangiogenic effects. We examined the effects of simvastatin on cardiac fibrosis and apoptosis in AM heterozygous knockout (AM +/À ) mice treated with angiotensin (Ang) II and high salt loading. Seven-weekold AM +/À mice were infused with Ang II while on a high-salt diet with or without simvastatin for 2 weeks. Hearts were stained by hematoxylin-eosin or Masson's trichrome, and were immunostained with isolectin B 4 and a-smooth muscle actin antibodies. Expression of c-Kit and Sca-1 messenger RNA (mRNA) was evaluated by real-time PCR analysis. Apoptotic cells in hearts were identified by terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL) staining. Hearts from Ang II/salt loading AM +/À mice showed marked perivascular fibrosis around coronary arteries. Treatment with simvastatin significantly inhibited the fibrosis around coronary arteries in Ang II/salt-loading AM +/À mice. Expression of c-Kit and Sca-1 mRNAs in hearts from Ang II/salt-loading AM +/À mice was significantly lower than in hearts from wild-type mice. Treatment with simvastatin significantly increased the suppressed expression of c-Kit and Sca-1 mRNAs. In addition, treatment with simvastatin significantly increased the number of isolectin B 4 -positive capillary arteries in hearts from Ang II/salt-loading AM +/À mice. Ang II/high salt significantly increased apoptotic cells in hearts from AM +/À mice; this trend was reversed by treatment with simvastatin. Thus, statins have potent cardioprotective effects that may be associated with anti-fibrotic, proangiogenic and anti-apoptotic effects in Ang II/salt-loading AM +/À mice.

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Effects of Atorvastatin on Angiogenesis in Hindlimb Ischemia and Endothelial Progenitor Cell Formation in Rats

Abstract: Atorvastatin strongly induced angiogenesis with increases in angiogenic cytokines, HO-1 and EPC numbers. Statins are thus considered potertial agents for therapeutic angiogenesis.

Cited by 50 publications

References 34 publications

Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

The angiopoietin/TIE receptor system: Focusing its role for ischemia-reperfusion injury

Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading

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