Exendin-4 Attenuates Remodeling in the Remote Myocardium of Rats After an Acute Myocardial Infarction by Activating ß-Arrestin-2, Protein Phosphatase 2A, and Glycogen Synthase Kinase-3 and Inhibiting ß-Catenin.

PURPOSE: This study tested if the protective anti-remodeling effect of GLP-1 agonist Exendin-4 after an acute myocardial infarction (MI) in rats involves inhibition of the Wnt1/ß-catenin signaling pathway. METHODS: Rats were divided into sham, sham + Exendin-4 (10 µg/day, i.p), MI, and MI + Exendin-4. MI was introduced to rats by permanent left anterior descending coronary artery (LAD) ligation. RESULTS: On day 7 post-infraction, MI rats showed LV dysfunction with higher serum levels of cardiac markers. Their remote myocardia showed increased mRNA and protein levels of collagen I/III with higher levels of reactive oxygen species (ROS) and inflammatory cytokines, as well as protein levels of Wnt1, phospho-Akt, transforming growth factor (TGF-ß1), Smad, phospho-Smad3, α-SMA, caspase-3, and Bax. They also showed higher protein levels of phospho-glycogen synthase kinase-3ß (p-GSK3ß), as well as total, phosphorylated, and nuclear ß-catenin with a concomitant decrease in the levels of cyclic adenosine monophosphate (cAMP), mRNA of manganese superoxide dismutase (MnSOD), and protein levels of Bcl-2, ß-arrestin-2, and protein phosphatase-2 (PP2A). Administration of Exendin-4 to MI rats reduced the infarct size and reversed the aforementioned signaling molecules without altering protein levels of TGF-1ß and Wnt1 or Akt activation. Interestingly, Exendin-4 increased mRNA levels of MnSOD, protein levels of ß-arrestin-2 and PP2A, and ß-catenin phosphorylation but reduced the phosphorylation of GSK3ß and Smad3, and total ß-catenin levels in the LV of control rats. CONCLUSION: Exendin-4 inhibits the remodeling in the remote myocardium of rats following acute MI by attenuating ß-catenin activation and activating ß-arrestin-2, PP2A, and GSK3ß. Graphical Abstract A graphical abstract that illustrates the mechanisms by which Exendin-4 inhibits cardiac remodeling in remote myocardium of left ventricle MI-induced rats. Mechanisms are assumed to occur in the cardiomyocytes and/or other resident cells such as fibroblast. Β-catenin activation and nuclear translocation are associated with increased synthesis of inflammatory cytokines and transforming growth factor ß-1 (TGF-ß1). GSK3ß is inhibited by phosphorylation at Ser9. Under normal conditions, ß-catenin is degraded in the cytoplasm by the active GSK3ß-dependent degradation complex (un-phosphorylated) which usually phosphorylates ß-catenin at Ser33/37/Thr41. After MI, TGF-ß1, and Wnt 1 levels are significantly increased, the overproduction of Wnt1 induces ß-catenin stabilization and nuclear translocation through increasing the phosphorylation of disheveled (DVL) protein which in turn phosphorylates and inhibits GSK3ß. TGF-ß1 stimulates the phosphorylation of Smad-3 and subsequent nuclear translocation to activate the transcription of collage 1/III and α-smooth muscle actin (α-SMA). Besides, TGF-ß1 stabilizes cytoplasmic ß-catenin levels indirectly by phosphorylation of Akt at Thr308-induced inhibition of GSK3ß by increasing phosphorylation of Ser9. Exendin-4, and possibly through G protein-coupled receptors (GPCRs), increases levels of cAMP and upregulates ß-arrestin-2 levels. Both can result in a positive inotropic effect. Besides, ß-arrestin-2 can stimulate PP2A to dephosphorylation Smad3 (inhibition) and GSK3ß (activation), thus reduces fibrosis and prevents the activation of ß-catenin and collagen deposition.

Electroencephalographic findings in epilepsy in Asir region of southern Saudi Arabia.

Electroencephalography plays an important role in the diagnosis and subsequent management of patients with epilepsy. We report the electroencephalographic findings in patients with epilepsy or history suggestive of epilepsy who were referred to the electroencephalographic unit of the major Psychiatric Hospital in Abha in the southwestern province of Saudi Arabia. Abnormal electroencephalographic finding was present in 50% of the referrals. Grand mal was by far the commonest type of epilepsy in our patients. The significance of our findings and the variation from other reported studies are discussed.

Full-term birth weight and placental morphology at high and low altitude.

OBJECTIVE: To study the association between placental morphology and full-term birth weight at high and low altitude. SUBJECTS: Twenty normal pregnant women living permanently at high altitude (3100 m) and 20 normal pregnant women living permanently at low altitude (500 m) in Southern Saudi Arabia. METHOD: For each subject in the two groups the mean hemoglobin concentration and hematocrit values throughout pregnancy were estimated and these were used as indices for maternal hypoxia. After delivery, the birth weight of each fetus was determined together with the placental weight. Placentas were then examined histologically using sections stained by periodic acid-Schiff and hematoxylin-eosin. The mean percentages of villi with syncytial knots, cytotrophoblastic cells and fetal capillaries were determined. RESULTS: The mean hemoglobin concentration and hematocrit values were significantly greater at high altitude than at low altitude (P < 0.001 for both). The mean birth weight and placental weight were significantly greater at low altitude compared to high altitude (P < 0.025 and 0.001, respectively). The placentas from high altitude showed histological changes suggestive of placental hypoxia i.e. significant increase in the incidence of syncytial knots, cytotrophoblastic cells and fetal capillaries at high altitude compared to low altitude (P < 0.005, 0.001 and < 0.05, respectively). At both high and low altitude the incidences of syncytial knots and cytotrophoblastic cells showed positive and significant correlations with mean maternal hemoglobin (r = 0.5 and 0.6, P < 0.01 and < 0.001, respectively) and hematocrit (r = 0.5 and 0.6, P < 0.01 and 0.001, respectively) during pregnancy and negative and significant correlations with fetal birth weight (r = -0.4 and -0.6, P < 0.01 and P < 0.001, respectively). CONCLUSION: The low birth weight observed at high altitude compared to low altitude appeared to be mainly secondary to placental hypoxia resulting from maternal hypoxia which in turn was caused by high altitude hypoxia.

Fat indices in high and low altitude populations in Southwestern Saudi Arabia.

The present study was undertaken to determine the fat indices in high and low altitude populations in Southwestern Saudi Arabia. Measurement of weight, height, mid-upper arm circumference, mid-upper arm muscle area, and skinfold thickness over the triceps region in 261 males living at high altitude (3150 meters above sea level) and 237 males living at low altitude (500 meters above sea level) in Southern Saudi Arabia are reported. The assessment of fatness by calculation of percent body weight is supported by correlation of triceps skinfold thickness with body mass index (BMI). In both high- and lowlanders the triceps skinfold thickness has significant correlation with BMI (P<0.001 for both). BMI also showed significant correlations with body weight, mid-upper arm circumference and mid-upper arm muscle area (P<0.001 for all). The findings show that the use of skinfold thickness in the prediction of degree of fatness in both groups seems to be a practical and useful method. However, it appears that there is a need for densitometric studies among Saudi populations to enable the derivation of valid regression equations for the calculation of body fat from skinfold thickness measurements. In the absence of skinfold measurements the BMI appeared to be a reliable indicator for assessment of body fat in Saudi high- and lowlanders.

High altitude and spontaneous preterm birth.

OBJECTIVE: To study the association between high altitude and spontaneous preterm birth. METHODS: Eleven placentas from cases of high altitude (3000 m) spontaneous preterm deliveries with no clinical predisposing cause were collected in Abha, a city of southern Saudi Arabia. The placentas were examined histologically using sections stained by periodic acid-Schiff and hematoxylin-eosin. The mean percentages of villi with syncytial knots and cytotrophoblastic cells were determined. RESULTS: Histology of the placenta samples showed an excessive formation of syncytial knots (45.4 +/- 13.3%) and cytotrophoblastic cells (52.7 +/- 15.2%) at terminal villi. CONCLUSION: The enhanced formation of syncytial knots and cytotrophoblastic cells is a histological feature of placental hypoxia, which may be secondary to maternal hypoxia resulting from high altitude hypoxia. Since placental hypoxia is associated with an increased incidence of spontaneous preterm birth, we suggest that high altitude may be involved in the etiology of spontaneous preterm birth.

Body composition and blood pressure: which indices of fatness show the strongest correlation?

We studied the strength of association of different indices of body composition with blood pressure (BP) in 430 healthy persons (222 males, 208 females) living in southern Saudi Arabia. The percentage of fat, fat mass (FM), fat mass index (FMI) and body mass index (BMI), but not the fat free mass (FFM) were greater in women than in men. All these indices were significantly correlated with BP except height and triceps fold thickness. However, the highest correlation with BP existed with the body weight, followed by FFM and BMI and the lowest correlation existed with FM and fat free index (FFI). Thus, this study showed that weight-related body composition indices are better correlated with BP than height-related ones. This may be of importance when addressing BP relation with the degree of fatness.

The association between strenuous physical activity and obesity in a high and low altitude populations in southern Saudi Arabia.

OBJECTIVES: To assess the relationship between obesity and strenuous physical activity in Saudi nationals living at high and low altitude. DESIGN: Cross-sectional randomized study. SUBJECTS: A total of 437 healthy adult Saudi nationals born and living permanently at high altitude (3150 m) and 468 healthy adult Saudi nationals born and living permanently at relatively low altitude 500 m). MEASUREMENTS: Body Mass Index (Weight (kg)/height (m2)) strenuous activity scores using Lipid Research Clinic Questionnaire. Resting radial pulse rate (beats/min). RESULTS: Strenuous physical activity was significantly and inversely associated with obesity in men at both high (chi 2 = 7.13, P < 0.05) and low (chi 2 = 6.14, P < 0.05) altitude but there was no clear trend for women at either altitude. The lack of association between strenuous physical activity and obesity in women was attributed to the low and homogeneous levels of strenuous physical activity. CONCLUSION: Strenuous physical activity should be encouraged as strategy directed towards weight reduction in obese as well as prevention of obesity in Saudi high and lowlanders.

Pattern of blood pressures among high and low altitude residents of southern Saudi Arabia.

The patterns of blood pressures and their correlates in 499 Saudi nationals aged 10-72 years living at high altitude (3150 m above sea level) and 594 Saudi nationals aged 10-76 years living at low altitude (500 m above sea level) were prospectively studied. The average BPs were significantly higher in highlanders compared with lowlanders. In both high and lowland residents the BPs rose with age although males in both groups showed a drop in both SBP and DBP beyond the age of 50 years. Hypertension (> 160/95 mmHg) was not detected among lowlanders and only 1.4% of all highlanders were found to be hypertensive. These differences in BPs are attributed to the significantly higher body mass index values and packed cell volume levels in the highlanders.

Relationship of body weight to altitude in Saudi Arabia.

Measurement of weight and height in 451 Saudi nationals ages 17 to 72 years, born and living permanently at high altitude (3150 meters) and Saudi nationals ages 17 to 76 years, born and living permanently at low altitude (500 meters) are reported. The native highlanders were significantly heavier (P<0.005 for men and <0.001 for women) and taller (P<0.001 for both men and women) than lowlanders. Body mass index (BMI=kg/m(2)) was used for assessment of normal weight, overweight or obesity, and underweight or thiness in the two communities. Only 30.8% of all highlanders and 34% of all lowlanders were found to have normal weight. The prevalence of overweight or obesity was significantly greater among highlanders (55.7%) than among lowlanders (42.9%) (P<0.01), while underweight or thiness was significantly more common among lowlanders (23.1%) as compared to highlanders (13.5%) (P<0.01). Among highlanders, overweight or obesity was significantly more common in women than men (P<0.01) while underweight or thiness was more common among men than women, although the difference was not statistically significant. This sex difference in the prevalence of overweight or obesity and underweight or thiness was not apparent among lowlanders. The percentage of overweight or obese highland and lowland men and women increased after the age of 39 years; conversely, the incidence of underweight or thiness in highland and lowland men and women decreased after the age of 39 years. The findings of this study indicate that overweight or obesity and, to a lesser extent, underweight or thiness are major nutritional problems in the two groups studied.

The location and properties of preganglionic vagal cardiomotor neurones in the rabbit.

The origins of preganglionic vagal neurons which slow the heart in the rabbit have been examined with standard neurophysiological stimulation and recording techniques. The activity of 216 neurones projecting to the right cervical vagus nerve have been recorded in localized areas of the brain stem. Thirty-six of these neurones were classified as cardiomotor neurones since they had properties similar to those described for such neurones in the cat. All had efferent axons in the range of B fibres. They could be synaptically activated by electrical stimulation of the ipsilateral aortic nerve which in the rabbit is solely barosensory. The majority of these neurones (70%) were spontaneously active and those which were normally silent could be made to fire by iontophoretic application of DL-homocysteic acid (an excitant amino acid). This spontaneous, or evoked, activity showed evidence of a pulse rhythm (of baroreceptor origin) and respiratory modulation (firing predominantly during expiration). In response to application of DL-homocysteic acid, the neuronal excitation was usually accompanied by a small but significant bradycardia. Histological examination showed that these neurones were located in both the dorsal vagal nucleus and the nucleus ambiguus.