Arly stages of development induces persistent sympathoexcitatory hyperresponsiveness with this fact possible mediating an early debut of hypertension [55]. Apoptosis and/or AN-3199 web angiotensin pathway activation, in addition to possibly mediate the impairment 22948146 of cardiac function by overfeeding, may also be involved in the deleterious effect of I/R in the heart [56]. Ischemia-reperfusion induced a reduction in myocardial contractility in rats from control litters. The reduction in myocardial contractility was assessed by developed left intraventricular pressure. In addition, vasoconstriction to angiotensin II and bradykinin induced endothelium-dependent relaxation were also decreased in response to I/R, suggesting that this condition causes damage in the myocardiocytes, vascular smooth muscle and endothelial cells, respectively [24]. These deleterious effects of I/R in the heart were correlated with increased expression of apoptotic markers. Angiotensin system may also be involved, as I/R increased the expression of angiotensinogen and of angiotensin AGTRa nd AGTR2 in control rats. However, in the hearts of early overfed rats, the deleterious effects of I/R were less marked than in control rats. Indeed, in overfed rats I/R did not significantly reduce myocardial contractility and the reduction in the coronary vasoconstriction to angiotensin II was less marked than in control rats. This may be related to the phenomenon called “the obesity paradox”, by which excess bodyweight may have a protective effect in cardiovascularEffects of Ischemia in Early OvernutritionFigure 6. Levels of B-cell lymphoma 2 (Bcl-2, (A)) and heat-shock protein 70 (Hsp-70,(B)) in the myocardium of control and overfed (overfed) rats subjected or not to 30 min of ischemia and 15 min of reperfusion (IR). Values are represented as mean 6S.E.M (n = 4?/ group). *P,0.05 vs control; #P,0.05 vs control-IR. doi:10.1371/journal.pone.0054984.order Licochalcone A gdisease [57]. Several hypothesis have been proposed to account for this phenomenon, like varying levels of tumor necrosis factor a (TNFa) [58]or B-type natriuretic peptide (BNP) [59]. In the present study, the hearts of overfed rats presented a marked increase in the expression of antiapoptotic markers such 
as Bcl-2 and Hsp-70. Also, in these rats I/R did not increase angiotensinogen gene expression in the heart and expression of angiotensin receptors was not only not increased but reduced after I/R. These changes may reduce I/R-induced myocardial and vasculardamage. It may be hypothesized that chronic activation of apoptosis and angiotensin system in overfed rats could induce long-term compensatory mechanisms that may reduce the impairment of myocardial contractility during I/R. In conclusion, both overfeeding and I/R impairs cardiac and coronary function due, at least in part, to activation of angiotensin pathway. However, overfeeding may reduce some of the harmful effects of I/R, which may be due to activation of compensatory mechanisms.Effects of Ischemia in Early OvernutritionFigure 7. Levels of inducible nitric oxide synthase (iNOS,(A)) and cyclooxigenase-2 (COX-2, (B)) in the myocardium of control and overfed (overfed) rats subjected or not to 30 min of ischemia and 15 min of reperfusion (IR). Values are represented as mean 6S.E.M (n = 4?/group). ***P,0.001 vs control; ##P,0.01 vs control-IR. doi:10.1371/journal.pone.0054984.gAcknowledgments??We are indebted to Maria Esther Martinez and Hortensia Fernandez?Lomana for their invaluable tech.Arly stages of development induces persistent sympathoexcitatory hyperresponsiveness with this fact possible mediating an early debut of hypertension [55]. Apoptosis and/or angiotensin pathway activation, in addition to possibly mediate the impairment 22948146 of cardiac function by overfeeding, may also be involved in the deleterious effect of I/R in the heart [56]. 
Ischemia-reperfusion induced a reduction in myocardial contractility in rats from control litters. The reduction in myocardial contractility was assessed by developed left intraventricular pressure. In addition, vasoconstriction to angiotensin II and bradykinin induced endothelium-dependent relaxation were also decreased in response to I/R, suggesting that this condition causes damage in the myocardiocytes, vascular smooth muscle and endothelial cells, respectively [24]. These deleterious effects of I/R in the heart were correlated with increased expression of apoptotic markers. Angiotensin system may also be involved, as I/R increased the expression of angiotensinogen and of angiotensin AGTRa nd AGTR2 in control rats. However, in the hearts of early overfed rats, the deleterious effects of I/R were less marked than in control rats. Indeed, in overfed rats I/R did not significantly reduce myocardial contractility and the reduction in the coronary vasoconstriction to angiotensin II was less marked than in control rats. This may be related to the phenomenon called “the obesity paradox”, by which excess bodyweight may have a protective effect in cardiovascularEffects of Ischemia in Early OvernutritionFigure 6. Levels of B-cell lymphoma 2 (Bcl-2, (A)) and heat-shock protein 70 (Hsp-70,(B)) in the myocardium of control and overfed (overfed) rats subjected or not to 30 min of ischemia and 15 min of reperfusion (IR). Values are represented as mean 6S.E.M (n = 4?/ group). *P,0.05 vs control; #P,0.05 vs control-IR. doi:10.1371/journal.pone.0054984.gdisease [57]. Several hypothesis have been proposed to account for this phenomenon, like varying levels of tumor necrosis factor a (TNFa) [58]or B-type natriuretic peptide (BNP) [59]. In the present study, the hearts of overfed rats presented a marked increase in the expression of antiapoptotic markers such as Bcl-2 and Hsp-70. Also, in these rats I/R did not increase angiotensinogen gene expression in the heart and expression of angiotensin receptors was not only not increased but reduced after I/R. These changes may reduce I/R-induced myocardial and vasculardamage. It may be hypothesized that chronic activation of apoptosis and angiotensin system in overfed rats could induce long-term compensatory mechanisms that may reduce the impairment of myocardial contractility during I/R. In conclusion, both overfeeding and I/R impairs cardiac and coronary function due, at least in part, to activation of angiotensin pathway. However, overfeeding may reduce some of the harmful effects of I/R, which may be due to activation of compensatory mechanisms.Effects of Ischemia in Early OvernutritionFigure 7. Levels of inducible nitric oxide synthase (iNOS,(A)) and cyclooxigenase-2 (COX-2, (B)) in the myocardium of control and overfed (overfed) rats subjected or not to 30 min of ischemia and 15 min of reperfusion (IR). Values are represented as mean 6S.E.M (n = 4?/group). ***P,0.001 vs control; ##P,0.01 vs control-IR. doi:10.1371/journal.pone.0054984.gAcknowledgments??We are indebted to Maria Esther Martinez and Hortensia Fernandez?Lomana for their invaluable tech.
