Enhanced development of azoxymethane-induced colonic preneoplastic lesions in hypertensive rats

Int J Mol Sci. 2013 Jul 15;14(7):14700-11. doi: 10.3390/ijms140714700.


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.

MeSH terms

  • Adipose Tissue / metabolism
  • Angiotensin II / blood
  • Animals
  • Azoxymethane / toxicity*
  • Carcinogens / toxicity*
  • Catalase / genetics
  • Catalase / metabolism
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Colorectal Neoplasms / pathology*
  • Cyclooxygenase 2 / blood
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Hypertension / pathology*
  • Insulin Resistance
  • Interleukin-6 / blood
  • Intestinal Mucosa / metabolism
  • Male
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress / drug effects*
  • Precancerous Conditions
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Rats, Zucker
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Carcinogens
  • Chemokine CCL2
  • Interleukin-6
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Angiotensin II
  • Catalase
  • Glutathione Peroxidase
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Azoxymethane