Heme Oxygenase-1 Protects Interstitial Cells of Cajal From Oxidative Stress and Reverses Diabetic Gastroparesis

Abstract

Background and Aims-Diabetic gastroparesis (delayed gastric emptying) is a well recognized complication of diabetes. Diabetic gastroparesis causes considerable morbidity and makes glucose control difficult. Kit-positive interstitial cells of Cajal (ICC) are required for normal gastric emptying. We hypothesized that there is a loss of Kit in diabetic gastroparesis due to elevated oxidative stress and that the elevated oxidative stress is due to low levels of heme oxygenase-1 (HO1), an important cytoprotective molecule against oxidative injury.

Hydrogen Sulfide, a Gaseous Transmitter, Stimulates Proliferation of Interstitial Cells of Cajal via Phosphorylation of AKT Protein Kinase

“…The presence of unrecognized factors, other than SCF, assists the survival of ICC under in vivo conditions. These may include NO (Choi et al 2007), CO (Choi et al 2008), 5-HT , insulin or IGF (insulin-like growth factor)-I (Horvath et al 2005), or IL-9 (Ye et al 2006. In the present study, in vitro experiments strongly suggest that H 2 S can directly affect ICC numbers.…”

“…A specific receptor tyrosine kinase (c-Kit) is a well-established marker for ICC, and stem cell factor (SCF), the ligand for c-Kit, is also required for the survival of established ICC (Huizinga et al 1995). This role may not be exclusive, or there may be varying capacities of compensating mechanisms, including signaling via other receptor tyrosine kinases and factors, such as NO (Choi et al 2007) and CO (Choi et al 2008), as mouse strains differ in their sensitivity to in vivo c-Kit blockade (Maeda et al 1992;Torihashi et al 1999). These apparent redundancies may, in fact, be cytoprotective for ICC.…”

Is Interstitial Cells of Cajal‒opathy Present in Gastroparesis?

“…Neuronal nitric oxide synthase-deficient (nNOS −/− ) mice and diabetic animals (eg, Streptozotocin treated rats, nonobese diabetic [NOD] mice, and ob/ob mouse model of obesity) are well-known animal models of GP. [19][20][21][22] The results observed in ICC deficient mice or rats were contradictory. They have been used both as a model of duodenogastric reflux based on the presence of a hypotensive pyloric sphincter, as well as delayed gastric emptying mimicking GP.…”

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

“…Mechanisms that contribute to pathophysiology of gastroparesis are variable, and gastric emptying profiles cannot specifically distinguish neuropathic from myopathic gastroparesis [3]. Other factors that have been implicated in pathogenesis include impaired glycemic control [4], abnormalities of interstitial cells of Cajal (ICCs) [5,6], alterations in immune infiltrate marked by increase in CD45 and CD68 immunoreactivity [5], decreased heme oxygenase-1 [7,8], and loss of neuronal nitric oxide synthase (nNOS) [5,7,9,10].…”