الفهرس 
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Abstract
This study was planned to investigate the possible cardioprotective effect of intermittent fasting (IF) in old rats subjected to acute myocardial infarction (MI) by isoproterenol and its underlying mechanisms, including heart and pancreatic autophagy.
The present work was carried out on 50 male Wistar rats (10 adults weighing 170-250 grams and 40 aged weighing 255-450 grams), which were divided into five groups:
group 1: Adult group (n=10):
group 2: Old group (n=10): Rats in both Adult and Old groups had free access to food and water-ad-libitum- for 4 weeks.
group 3: Old-intermittent fasting group; Old-F (n=10): Rats in this group were submitted to alternate day fasting. They were fed ad libitum every other day and fasted the following day with free access to water for 4 weeks. On the fasting day, the cages were changed to avoid the presence of remaining pellets.
Rats in Adult, Old and Old-F groups were injected with saline for two days at 24 hours interval (on day 27th and 28th).
group 4: Old-isoproterenol group; Old-ISO (n=10):
Rats in this group had free access to food and water-ad-libitum- for 4 weeks, then were injected subcutaneously by isoproterenol in a dose of 85 mg/Kg body weight for two days at 24 hours interval (on 27th and 28th day) to induce myocardial infarction.
group 5: Old-intermittent fasting-isoproterenol group; Old-F-ISO (n=10): Rats in this group were submitted to fast every other day for 4 weeks as in group 3, then were injected by isoproterenol as in group 4.
All rats were assessed for the changes in body weight (BW); body mass index (BMI); waist circumference (WC); visceral adipose tissue weight (VATW); visceral adipose tissue weight/body weight (VATW/BW); glucose homeostasis parameters, including fasting plasma glucose (FPG), plasma level of fasting insulin (FI), homeostatic model assessment of insulin resistance ( HOMA-IR), and homeostatic model assessment of β-cell function (HOMA-%B), pancreatic autophagy marker, mRNA expression of pancreatic Atg-7; plasma levels of lipid profile, namely triglycerides (TGs), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C),and high density lipoprotein cholesterol (HDL-C); atherogenic index (AI); liver weight (LW) and Liver index; cardiac parameters namely, cardiac injury markers [plasma level of troponin-I, and creatine kinase myocardial band (CK-MB)], cardiac level of oxidative stress markers [malondialdehyde (MDA), reduced glutathione (GSH)], cardiac level of proinflammatory marker [tumor necrosis factor -alpha (TNF-α)], and cardiac autophagy marker [mRNA expression of heart Atg-5]. Histopathological changes in cardiac muscle and liver tissues were also determined.
The results of this study revealed that Old rat group compared to Adult rats showed a significant increase in the initial and final BW, BMI, and WC, while there was a significant decrease in % BW. FI was significantly decreased, associated with a higher FPG and a lower HOMA-%B, though both were statistically insignificant. The mRNA expression of pancreatic autophagy marker Atg-7 and HOMA-IR were not significantly different compared to Adult rats. Moreover, there was a significant increase in plasma levels of TGs, TC, LDL-C and atherogenic index, along with non-significant decrease of HDL-C. Liver weight was significantly increased, while liver index showed non-significant change in all old groups versus Adult group. The plasma level of troponin-I was significantly higher, while CK-MB was not significantly different. The heart level of GSH was significantly lower, while the heart levels of MDA and TNF-α, as well as the mRNA expression of the cardiac autophagy marker Atg-5 were not significantly different in Old group versus Adult group.
Compared to Old group, the Old-ISO rat group showed non-significant change in FPG and FI levels. The mRNA expression of pancreatic Atg-7 was significantly increased in Old-ISO group versus Old group, becoming significantly higher than that of the Adult value. HOMA-IR and HOMA-%B showed non-significant changes. The levels of TGs, TC, LDL-C, AI were significantly decreased, while HDL-C was significantly elevated approaching those of the Adult group. Plasma levels of Troponin-I and CK-MB, as well as, cardiac tissue levels of MDA, TNF-α, and the mRNA expression of Atg-5 were significantly elevated in Old-ISO group compared to both Old and Adult groups. Heart level of GSH was not significantly affected in Old-ISO group versus Old group or Adult group.
Intermittent fasting in Old-F and in Old-F-ISO groups induced significant reduction of % BMI, % BW, VATW and VATW/BW compared to Old and Old-ISO groups and even all became significantly lower than those of Adult group. FPG was significantly decreased, while FI levels showed non-significant increase compared to Old and Old-ISO groups, and FI was still significantly lower than that of the Adult value. The mRNA expression of pancreatic Atg-7 was significantly increased compared to Old group and Adult group. HOMA-IR was significantly decreased in Old-F-ISO compared to Adult group. HOMA-%B was significantly increased in Old-F group versus Old group, and in Old-F-ISO group versus Old and Adult groups. The levels of TGs, TC, and LDL-C and AI were significantly diminished, while HDL-C level was significantly elevated in Old-F and Old-F-ISO groups compared to Old and Adult groups. Also, Old-F-ISO group presented a significantly lower LDL-C and AI along with a significant increase in HDL-C compared to Old-ISO group. Troponin-I and CK-MB were not significantly altered in Old-F group versus Old and Adult groups, but they were significantly decreased in Old-F-ISO group compared to Old-ISO group, approaching those of the Adult values. The cardiac levels of MDA, GSH, and TNF-α were not significantly changed in Old-F compared to Old group, but the MDA and TNF-α were significantly higher than the Adult values. The MDA and TNF- α were significantly decreased in Old-F-ISO group compared to Old-ISO group, reaching levels comparable to those of the Adult group. GSH showed a significant increase in Old-F-ISO compared to Old group, but was not significantly changed when compared to Old-ISO group. The mRNA expression of the cardiac autophagy marker Atg-5 was significantly elevated in Old-F rats versus Old group, and was significantly elevated in Old-F-ISO groups when compared to both Old and Adult groups, but it was not significantly different from Old-ISO group.
Histopathological studies of left ventricles revealed that, Old group showed a mild to moderate inflammatory changes. IF can inhibit all the histological inflammatory markers in Old-F group compared to Old rats namely, the blood vessels congestion, edema and hemorrhage. IF alleviated the local inflammatory response in Old-F-ISO versus Old-ISO group as manifested histologically by the attenuation of edema.
Histopathological studies of liver sections denoted the development of liver steatosis in all old rat groups. Histopathological scoring revealed mild steatosis in Old group and moderate steatosis in Old-F, Old-ISO and Old-F-ISO groups.
In conclusion, the results of the present study provide evidence that IF was effective in increasing the tolerance of aged myocardium to acute cardiac insult. This cardioprotective effect might be achieved via attenuating the age-related obesity, dyslipidemia and diabetic changes. Moreover, chronic activation of heart and pancreatic autophagy by IF might provide a potential cardioprotective effect, whereas acute activation of both significantly promote cardiac injury. Further researches are needed to prove the cardioprotective effect of heart and pancreatic autophagy activation in aged individuals.