Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxidative stress.

Hyperglycemia is an indication of poor outcome for heart attack patients, even for nondiabetic patients with stress-induced hyperglycemia. Previous studies showed that inhibition of aldose reductase, the first and rate-limiting enzyme of the polyol pathway, attenuated contractile dysfunction in diabetic animals, but the mechanism is unclear. We therefore wanted to find out whether the polyol pathway also contributes to acute hyperglycemia-induced cardiac contractile dysfunction, and determine the mechanism involved. Rat hearts were isolated and retrogradely perfused with Krebs buffer containing either normal or high concentrations of glucose for 2 h. Short exposure to high-glucose medium led to contractile dysfunction as indicated by decreased -dP/dt(max), as well as elevation in left ventricular end-diastolic pressure. Cardiomyocytes incubated in high-glucose medium showed abnormal Ca2+ signaling, most likely because of decreased activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) inactivated by oxidative stress. Inhibition of aldose reductase or sorbitol dehydrogenase, the second enzyme in the polyol pathway, ameliorated contractile dysfunction, attenuated oxidative stress, and normalized Ca2+ signaling and SERCA activity caused by high glucose, indicating that the polyol pathway is the major contributor to acute hyperglycemia-induced oxidative stress leading to the inactivation of SERCA and contractile dysfunction.

Cardioprotection by the female sex hormone -- interaction with the beta1-adrenoceptor and its signaling pathways.

Estrogen is a steroid and the predominant female sex hormone in the body. Ovariectomised (OVX) adult female rats exhibit greater myocardial injury compared to the sham rats following ischemic insult in the presence of beta-adrenoceptor stimulation. Estrogen replacement restores the response of OVX female rats to ischemic/beta-adrenoceptor stimulation to that of normal female rats, providing evidence for a cardioprotective role of estrogen during ischemic insult. The protective effect is due to down-regulation of the beta(1)-adrenoceptor. There is also evidence that estrogen suppresses the expression and activity of protein kinase A (PKA), a second messenger of the G(s) protein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile function. There is also preliminary evidence that estrogen may suppress the activity of Ca(2+)/calmodulin kinase II deltac isoform (CaMKII-deltac), another downstream second messenger of the beta(1)-adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration of estrogen at physiological level could inhibit myocardial beta(1)-adrenoceptor and attenuate Ca(2+) influx independent of the estrogen receptor. In addition, brain studies also show estrogen inhibits the activities activated by the beta-adrenoceptor in brain regions responsible for the regulation of arterial blood pressure. Thus, it can be appreciated that the interaction between estrogen and the beta(1)-adrenoceptor and its signaling pathways is a complex one. Estrogen plays an important role not only in reproduction but also in other regulatory functions such as cardioprotection.