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Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation.

Lenarczyk M, Su J, Haworth ST, Komorowski R, Fish BL, Migrino RQ, Harmann L, Hopewell JW, Kronenberg A, Patel S, Moulder JE, Baker JE - Pharmacol Res Perspect (2015)

Bottom Line: TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis.Simvastatin mitigated these morphological injuries.Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiothoracic Surgery, Medical College of Wisconsin Milwaukee, Wisconsin.

ABSTRACT
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

No MeSH data available.


Related in: MedlinePlus

Simvastatin and liver function. (A) Liver function at 120 days after TBI compared with age-matched sham-irradiated control animals. The horizontal line represents value for age matched, sham-irradiated control rats. (B) Morphological changes in the liver at 120 days after TBI (H&E staining). (C) Quantitative RT-PCR analysis of gene expression in liver after 10 Gy TBI. The identities of the genes are described in the table. Livers were examined at 20 and 60 days post irradiation. Data shown as means + SD, n = 3–6/group. *P < 0.05, vs. control. TBI, total body irradiation; H&E, hematoxylin and eosin; PCR, polymerase chain reaction.
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fig02: Simvastatin and liver function. (A) Liver function at 120 days after TBI compared with age-matched sham-irradiated control animals. The horizontal line represents value for age matched, sham-irradiated control rats. (B) Morphological changes in the liver at 120 days after TBI (H&E staining). (C) Quantitative RT-PCR analysis of gene expression in liver after 10 Gy TBI. The identities of the genes are described in the table. Livers were examined at 20 and 60 days post irradiation. Data shown as means + SD, n = 3–6/group. *P < 0.05, vs. control. TBI, total body irradiation; H&E, hematoxylin and eosin; PCR, polymerase chain reaction.

Mentions: Serum AST activity at 120 days after TBI, was decreased compared with sham-irradiated rats. Simvastatin restored AST levels in irradiated rats to sham-irradiated control levels, and had no significant effect on sham-irradiated rats. Serum ALT levels were unaffected by TBI or simvastatin administration (Fig.2A). Total bilirubin levels were increased 120 days after TBI compared with sham-irradiated rats. Simvastatin completely mitigated this increase in bilirubin levels in irradiated rats back down to control levels. Simvastatin had no effect alone on sham-irradiated rats. Serum alkaline phosphatase activity was decreased at 120 days following TBI, compared with sham-irradiated rats. Simvastatin partially reversed this decline in alkaline phosphatase activity in irradiated rats and had no effect on sham-irradiated rats (Fig.2A).


Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation.

Lenarczyk M, Su J, Haworth ST, Komorowski R, Fish BL, Migrino RQ, Harmann L, Hopewell JW, Kronenberg A, Patel S, Moulder JE, Baker JE - Pharmacol Res Perspect (2015)

Simvastatin and liver function. (A) Liver function at 120 days after TBI compared with age-matched sham-irradiated control animals. The horizontal line represents value for age matched, sham-irradiated control rats. (B) Morphological changes in the liver at 120 days after TBI (H&E staining). (C) Quantitative RT-PCR analysis of gene expression in liver after 10 Gy TBI. The identities of the genes are described in the table. Livers were examined at 20 and 60 days post irradiation. Data shown as means + SD, n = 3–6/group. *P < 0.05, vs. control. TBI, total body irradiation; H&E, hematoxylin and eosin; PCR, polymerase chain reaction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492761&req=5

fig02: Simvastatin and liver function. (A) Liver function at 120 days after TBI compared with age-matched sham-irradiated control animals. The horizontal line represents value for age matched, sham-irradiated control rats. (B) Morphological changes in the liver at 120 days after TBI (H&E staining). (C) Quantitative RT-PCR analysis of gene expression in liver after 10 Gy TBI. The identities of the genes are described in the table. Livers were examined at 20 and 60 days post irradiation. Data shown as means + SD, n = 3–6/group. *P < 0.05, vs. control. TBI, total body irradiation; H&E, hematoxylin and eosin; PCR, polymerase chain reaction.
Mentions: Serum AST activity at 120 days after TBI, was decreased compared with sham-irradiated rats. Simvastatin restored AST levels in irradiated rats to sham-irradiated control levels, and had no significant effect on sham-irradiated rats. Serum ALT levels were unaffected by TBI or simvastatin administration (Fig.2A). Total bilirubin levels were increased 120 days after TBI compared with sham-irradiated rats. Simvastatin completely mitigated this increase in bilirubin levels in irradiated rats back down to control levels. Simvastatin had no effect alone on sham-irradiated rats. Serum alkaline phosphatase activity was decreased at 120 days following TBI, compared with sham-irradiated rats. Simvastatin partially reversed this decline in alkaline phosphatase activity in irradiated rats and had no effect on sham-irradiated rats (Fig.2A).

Bottom Line: TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis.Simvastatin mitigated these morphological injuries.Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiothoracic Surgery, Medical College of Wisconsin Milwaukee, Wisconsin.

ABSTRACT
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

No MeSH data available.


Related in: MedlinePlus