Abstract
Metabolic syndrome is associated with an increased risk of colorectal cancer. This study investigated the impact of hypertension, a component of metabolic syndrome, on azoxymethane (AOM)-induced colorectal carcinogenesis using SHRSP/Izm (SHRSP) non-diabetic/hypertensive rats and SHRSP.Z-Leprfa/IzmDmcr (SHRSP-ZF) diabetic/hypertensive rats. Male 6-week-old SHRSP, SHRSP-ZF, and control non-diabetic/normotensive Wister Kyoto/Izm (WKY) rats were given 2 weekly intraperitoneal injections of AOM (20 mg/kg body weight). Two weeks after the last injection of AOM, the SHRSP and SHRSP-ZF rats became hypertensive compared to the control WKY rats. Serum levels of angiotensin-II, the active product of the renin-angiotensin system, were elevated in both SHRSP and SHRSP-ZF rats, but only the SHRSP-ZF rats developed insulin resistance, dyslipidemia, and hyperleptinemia and exhibited an increase in adipose tissue. The development of AOM-induced colonic preneoplastic lesions and aberrant crypts foci, was significantly accelerated in both SHRSP and SHRSP-ZF hypertensive rats, compared to WKY normotensive rats. Furthermore, induction of oxidative stress and exacerbation of inflammation were observed in the colonic mucosa and systemically in SHRSP and SHRSP-ZF rats. Our findings suggest that hypertension plays a role in the early stage of colorectal carcinogenesis by inducing oxidative stress and chronic inflammation, which might be associated with activation of the renin-angiotensin system.
Highlights
Obesity-related systemic metabolic dysfunctions such as diabetes mellitus, hypertension, and dyslipidemia are collectively known as metabolic syndrome (Mets) and pose serious health problems throughout the world [1,2]
The objective of this study was to determine the susceptibility of SHRSP-Zucker Fatty (ZF) and SHRSP rats to azoxymethane (AOM)-induced colorectal carcinogenesis and the utility of these rats as models for Mets, in particular, as models for hypertension-associated colorectal carcinogenesis, that appropriately reflect the pathological conditions of human Mets
There was a significant increase in the mean adipose tissue weights in SHRSP-ZF rats compared to Wister Kyoto/Izm (WKY) (p < 0.001)
Summary
Obesity-related systemic metabolic dysfunctions such as diabetes mellitus, hypertension, and dyslipidemia are collectively known as metabolic syndrome (Mets) and pose serious health problems throughout the world [1,2]. In addition to the morbidity associated with these metabolic disorders, recent studies have revealed that Mets is linked to an increased risk of cancer in several organ sites including the colorectum [3,4,5,6,7,8]. Several pathophysiological mechanisms for this association have been described, including the emergence of insulin resistance, the state of chronic inflammation, induction of oxidative stress, and occurrence of adipokine imbalance [5,6]. There is increasing evidence that the renin-angiotensin system may have paracrine and autocrine functions with regard to tissue oxidative stress and chronic inflammation, as well as cellular proliferation and apoptosis [10,11,12,13,14]. The precise mechanisms by which hypertension plays a role in the early stage of colorectal carcinogenesis remain unclear
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