Sophie Besse

Senescent Heart Compared With Pressure Overload–Induced Hypertrophy

Although systolic left ventricular (LV) function is normal in the elderly, aging is associated in rat papillary muscle with mechanical and sarcoplasmic reticulum Ca2+ ATPase alterations similar to those observed in the hypertrophied heart. However, alterations in the other calcium-regulating proteins implicated in contraction and relaxation are still unknown. To investigate alterations in LV function and calcium-regulating proteins, we measured hemodynamics and Na(+)-Ca2+ exchanger (NCx), ryanodine receptor (RyR2), and sarcoplasmic reticular Ca2+ ATPase (SERCA2) mRNA levels (expressed in densitometric scores normalized to that of poly(A+) mRNA) in left ventricle from 4-month-old (adult, n = 13) and 24-month-old (senescent, n = 15) rats. For ex vivo contractile function, active tension was measured during isolated heart perfusion in adult (n = 11) and senescent (n = 11) rats. For comparison of age-dependent effects of moderate hypertension on both hemodynamics and calcium proteins, renovascular hypertension was induced or a sham operation performed at 2 (n = 11 and n = 6) and 22 (n = 26 and n = 5) months of age. In senescent rats, LV systolic pressure and maximal rates of pressure development were unaltered, although active tension was depressed (4.7 +/- 0.4 versus 8.3 +/- 0.7 g/g heart weight in adults, P < .0001). SERCA2 mRNA levels were decreased in senescent left ventricle (0.98 +/- 0.05 versus 1.18 +/- 0.05 in adults, P < .01), without changes in NCx and RyR2 mRNA accumulation. Renovascular hypertension resulted in 100% mortality in aged rats; in adults, renovascular hypertension resulted, 2 months later, in an increase of LV systolic pressure (170 +/- 7 versus 145 +/- 3 mm Hg in sham-operated rats, P < .05) and in mild LV hypertrophy (+18%, P < .01) associated with a decrease in SERCA2 mRNA levels (1.02 +/- 0.03 versus 1.18 +/- 0.03 in sham-operated rats, P < .001). Contractile dysfunction in senescent isolated heart and decreased SERCA2 mRNA levels were associated with in vivo normal LV function at rest, indicating the existence of in vivo compensatory mechanisms. RyR2 and NCx gene expressions were not implicated in the observed contractile dysfunction. In aged rats, renovascular hypertension resulted in 100% mortality, probably related to elevated levels of circulating angiotensin II, whereas in adult rats, renovascular hypertension induced a mild LV hypertrophy associated with a selective alteration in SERCA2 gene expression.

Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts

OBJECTIVEnBoth aging and myocardial ischemia are associated with alterations of calcium-regulating proteins. We investigated the effects of graded levels of low-flow ischemia on myocardial function and on SR Ca(2+)-ATPase (SERCA2), Na(+)-Ca2+ exchanger (NCX) and ryanodine receptor (RyR2), at mRNA and protein levels in both adult and senescent myocardium.nnnMETHODSnIsolated hearts from 4 and 24 month old (mo) rats were retrogradely perfused during 180 min at 100% (100% CF, n = 11 and n = 11 respectively. 30% (30% CF, n = 10 and n = 12) or 15% (15% CF, n = 13 and n = 8) of their initial coronary flow, and active tension and coronary resistance (in % of their baseline value) were recorded. After 180 min of perfusion. NCX, RyR2 and SERCA2 mRNAs (in % of age-matched 100% CF group value) and protein levels were quantitated in the left ventricles by slot blot and Western blot analysis, respectively.nnnRESULTSnIn 24 mo hearts, low-flow ischemia induced a greater fall in active tension (-65 +/- 7% vs. -40 +/- 4% in 4 mo 30% CF, p, 0.01 and -82 +/- 2% vs. -60 +/- 5% in 4 mo 15% CF groups, p < 0.05 after 15 min of ischemia) and a greater increase in coronary resistance (+357 +/- 44% vs. +196 +/- 39% in 4 mo 30% CF, p < 0.05 and +807 +/- 158% vs. +292 +/- 61% in 4 mo 15% CF groups, p < 0.001 after 15 min of ischemia). An increased accumulation of SERCA2 (+36% and NCX (+46%) transcripts, but not RyR2, already occurred in 24 mo 30% CF group while the 3 transcripts accumulated in 24 mo 15% CF group. In 4 mo rats SERCA2 (+26%), NCX (+35%) and RyR2 (+81%) mRNA levels only increased in the 15% CF group. Corresponding calcium-regulating protein levels were unaltered whatever the degree of flow reduction in both 4 mo and 24 mo hearts.nnnCONCLUSIONnLow-flow ischemia does not induce calcium-regulating protein loss in both adult and senescent hearts. The increase in mRNAs coding for calcium-handling proteins and the impairment of myocardial function which occur at a lesser degree of coronary flow reduction in senescent hearts, indicate a higher vulnerability to low-flow ischemia during aging.

Age-dependent changes in myocardial susceptibility to zero flow ischemia and reperfusion in isolated perfused rat hearts: relation to antioxidant status

Ageing is associated with an increase in myocardial susceptibility to ischemia and a decrease in post-ischemic recovery of function. In the present study, we have examined the effects of ageing on (i) myocardial ischemic contracture, (ii) the reperfusion syndrome and lipid peroxidation upon reperfusion, and (iii) the activity of enzymes involved in reactive oxygen species elimination. Hearts from male Wistar rats aged 4 (adults), 16 (old) or 24 months (senescent) were subjected to 20-min zero flow ischemia and 30-min reperfusion ex vivo. Cardiac activity of superoxide dismutase, catalase, and glutathione peroxidase, as well as cardiac content of thiobarbituric acid reactants were assessed in frozen heart samples. The effects of ageing on ischemic contracture of the sarcomeres were assessed on electromicrographs of tissues taken at the end of ischemia. In our experimental conditions, ischemic contracture of the sarcomeres increased progressively during ageing. In contrast, the severity of the reperfusion syndrome increased between 4 and 16 months of age, and then decreased up to 24 months of age. We propose that the peak of susceptibility of the myocardium to reperfusion observed during moderate ageing might be related to a decrease in the ability of cardiomyocytes to dismutate hydrogen peroxide as suggested by the observed decrease in catalase activity. Finally, the better resistance to the reperfusion syndrome exhibited by senescent rats compared to old rats might be due to a natural selection of a subpopulation of rats which is particularly resistant to oxidative stress.

Ageing exacerbates the cardiotoxicity of hydrogen peroxide through the Fenton reaction in rats

Reactive oxygen species (ROS) are involved in the post-ischemic reperfusion syndrome of the myocardium. Moreover, ageing is associated with an increased cardiac sensitivity to both ischemia and reperfusion. The aim of the present study was to determine whether the lower tolerance of aged hearts to reperfusion could be due to an increased sensitivity to the ROS that are produced during the early phase of reperfusion. For this purpose isolated perfused hearts from adult (4 months) and aged (24 months) rats were perfused with a buffer containing 150 microM of hydrogen peroxide (H(2)O(2)) in presence or absence of deferoxamine mesylate (150 microM), an iron chelator. H(2)O(2) perfusion was continued until left ventricular developed pressure had decreased up to 20% of its initial value. Ageing led to a significant reduction of the duration of the H(2)O(2) perfusion required for inducing a 80% functional alteration. Although deferoxamine did not affect this parameter in adult rats, it significantly increased the duration of H(2)O(2)-perfusion in senescent hearts (control: 14.0+/-0.9 min vs. deferoxamine: 18.1+/-1.0, P<0.05). Similarly, ageing aggravated cardiac contracture induced by H(2)O(2)-perfusion. Again, deferoxamine, which had no effect on this parameter in young adult hearts, significantly reduced the contracture of senescent rat hearts. To conclude, our data clearly show that ageing is associated with an increased sensitivity of the myocardium to hydrogen peroxide, which is partly reversed by iron chelation. These results suggest that the iron-catalyzed Fenton reaction producing hydroxyl radicals might be greater in hearts from senescent rats than in hearts from young adults.

Diet and Heart Health: Moderate Wine Drinking Strengthens the Cardioprotective Effects of Fish Consumption

Growing evidence indicates that the Mediterranean diet is beneficial to human health. Many epidemiological and research studies have reported that this diet pattern is able to limit the development and progression of coronary heart disease, one of the leading cause of morbidity and mortality in both developed and developing countries worldwide. There is now a large consensus about recommending Mediterranean diet to reduce atherosclerosis and coronary artery disease and to limit the risk of fatal complications such as sudden cardiac death and heart failure. This review underlines the role of two of the specific components of the Mediterranean diet, namely marine omega-3 fatty acids and wine, and the link between moderate wine consumption and fatty acid profiles.

Effects of fasting and exogenous glucose delivery on cardiac tolerance to low-flow ischemia in adult and senescent rats

Metabolic disorders due to changes in cytosolic glucose utilisation are suspected to be involved in the increased sensitivity of the aged myocardium to ischemia. This study presents the first direct measurement of glucose utilisation in hearts from senescent rats during low-flow ischemia under different conditions of substrate delivery and glycogen stores. Isolated hearts from young adult (4-months-old) and senescent (24-months-old) rats were subjected to 30 min coronary flow restriction (residual flow rate=2% of control flows). Experiments were performed using glucose-free or glucose-enriched (11 mmol/L) perfusion media. The effects of increased glycogen stores were assessed after 24-h fasting in both age groups. Ischemic contracture was measured via a left-ventricular balloon. Ageing increased ischemic contracture under both conditions of substrate delivery in fed rat hearts. The increase in ischemic tolerance induced by fasting in senescent rat hearts was less than that seen in young rat hearts. Moreover, fasting decreased glucose utilisation in hearts from young rats, an effect which was not found in hearts from old rats. Furthermore, myocardial glycogen utilisation was increased in all groups of aged rats compared with that of young adults, particularly under fasting conditions. It is concluded that fasting is less detrimental to the aged myocardium during low-flow ischemia than to the young myocardium because it does not further reduce exogenous glucose utilisation, and it stimulates glycogen consumption. Moreover, a reduction in exogenous glucose utilisation, which is only partly compensated for by increased glycogenolytic flux could be, at least in part, responsible for the increased ischemic contracture in hearts from old fed rats. Finally, our glucose-free experiments suggest that residual oxidative phosphorylation during low-flow ischemia might be less relevant in hearts from senescent rats than in those from young adults.

Relationship between Antioxidant Enzyme Activities and Cardiac Susceptibility to Ischaemia and Reperfusion during Aging in Rats

Numerous studies have shown that ischaemic damage and the so called reperfusion syndrome of the myocardium are, at least in part, associated to a burst of oxygen-derived free radicals (1). The involvement of reactive oxygen species (ROS) in post-ischaemic contractile dysfunction is supported by several studies underlying the benefit of the use of antioxidant catalytic agents such as Superoxide dismutase and/or catalase during experimental cardiac reperfusion (2,3). Endogenous catalytic ROS scavengers, namely Superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx) and glutathione reductase (GRx) play key roles in the cellular defence systems against ROS under pathophysiological conditions (3–5). The myocardial activity of these enzymes is therefore determinant to protect the heart during post-ischaemic reperfusion. It is now well established that ageing is associated to an increase in cardiac susceptibility to ischaemia (6) and reperfusion (7) in rats. The present study was designed to define the relationship between the endogenous antioxidant status and cardiac susceptibility to ischaemia and reperfusion during ageing.