The heme oxygenase system attenuates pancreatic lesions and improves insulin sensitivity and glucose metabolism in deoxycorticosterone acetate hypertension

Abstract

Recent clinical reports indicate that impaired glucose tolerance is a common phenomenon in primary aldosteronism. Aldosterone stimulates NF-κB and activating protein-1 (AP-1) to cause oxidative injury. Elevated oxidative stress impairs insulin signaling. We recently showed that the heme oxygenase (HO) system lowers blood pressure (BP) in deoxycorticosterone-acetate (DOCA)+salt hypertension, a model of primary aldosteronism. However, the effect of the HO system on insulin sensitivity in this model remains largely unclear. Here we report the effects of the HO-inducer hemin and the HO-blocker [chromium mesoporphyrin (CrMP)] on insulin sensitivity/glucose metabolism. Our experimental design included the following 10 groups: (A) controls [(i) surgery-free or normal Sprague-Dawley (SD), (ii) uninephrectomized (UnX)-sham, (iii) UnX+salt (0.9%NaCl+0.2%KCl) and (iv) UnX+DOCA]; (B) DOCA+salt; (C) hemin+DOCA+salt; (D) hemin+CrMP+DOCA+salt; (E) CrMP+DOCA+salt; (F) vehicle-treated rats and (G) normal SD+hemin. Hemin therapy lowered BP and increased plasma insulin and the insulin-sensitizing protein adiponectin with slight but significant reduction of glycemia, while CrMP abolished the hemin effects. Furthermore, hemin improved intraperitoneal glucose and insulin tolerance, suggesting that although DOCA+salt-hypertensive rats were normoglycemic, insulin signaling may be impaired. In contrast, the HO-inhibitor CrMP aggravated insulin resistance and exacerbated glucose and insulin tolerance. Interestingly, the enhanced insulin sensitization in hemin-treated animals was accompanied by reduced urinary/gastrocnemius muscle 8-iso-prostaglandin F2α (8-isoprostane), inflammatory/oxidative transcription factors like NF-κB, AP-1, JNK, and heme content, whereas HO-1, HO-activity, cGMP, and plasma/gastrocnemius muscle antioxidants including bilirubin, ferritin, SOD, catalase, and the total antioxidant capacity were increased. Similarly, hemin enhanced pancreatic HO, cGMP, and cAMP but suppressed 8-isoprostane and attenuated pancreatic histopathological lesions including fibrosis, interstitial edema, acinar cell necrosis, vacuolization, and mononuclear cell infiltration, with corresponding improvement of insulin production. Our results suggest that impaired insulin signaling may be a forerunner to hyperglycemia in aldosteronism. By preserving pancreatic morphology, potentiating insulin signaling, and lowering BP, the HO system may prevent metabolic and cardiovascular complications in aldosteronism.