Effects of Human C-Reactive Protein on Pathogenesis of Features of the Metabolic Syndrome

Abstract

Major controversy exists as to whether increased C-reactive protein (CRP) contributes to individual components of the metabolic syndrome or is just a secondary response to inflammatory disease processes. We measured blood pressure and metabolic phenotypes in spontaneously hypertensive rats (SHR) in which we transgenically expressed human CRP in liver under control of the apoE promoter. In SHR transgenic rats, serum levels of human CRP approximated the endogenous levels of CRP normally found in the rat. Systolic and diastolic blood pressures measured by telemetry were 10–15 mmHg greater in transgenic SHR expressing human CRP than in SHR controls (P<0.01). During oral glucose tolerance testing, transgenic SHR exhibited hyperinsulinemia compared to controls (insulin area under the curve 36±7 versus 8±2 nmol/L/2h, respectively, P<0.05). Transgenic SHR also exhibited resistance to insulin stimulated glycogenesis in skeletal muscle (174±18 versus 278±32 nmol glucose/g/2h, P<0.05), hypertriglyceridemia (0.84±0.05 versus 0.64±0.03 mmol/L, P<0.05), reduced serum adiponectin (2.4±0.3 versus 4.3±0.6 mmol/L, P<0.05), and microalbuminuria (200±35 versus 26±5 mg albumin/g creatinine, respectively, P<0.001). Transgenic SHR had evidence of inflammation and oxidative tissue damage with increased serum levels of interleukin 6 (IL6) (36.4±5.2 versus 18±1.7 pg/ml, P<0.005) and increased hepatic and renal TBARS (1.2±0.09 versus 0.8±0.07 and 1.5±0.1 versus 1.1±0.05 nM/mg protein, respectively, P<0.01), suggesting that oxidative stress may be mediating adverse effects of increased human CRP. These findings are consistent with the hypothesis that increased CRP is more than just a marker of inflammation and can directly promote multiple features of the metabolic syndrome.

Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats

“…Therefore, in the current study in an animal model with inflammatory and metabolic disturbances induced by transgenic expression of human CRP, we tested the anti-inflammatory, antioxidative, and metabolic effects of Fumaderm, a preparation of fumaric acid esters containing DMF. We found that in the SHR-CRP rat model in which inflammation is known to be caused by increased expression of human CRP [3], FAE treatment was associated with significant anti-inflammatory effects despite the fact that treatment did not reduce circulating levels of transgenic human CRP. These findings are consistent with the possibility that FAE is protecting against the pro-inflammatory effects of human CRP.…”

“…Inflammation and oxidative stress play important roles in the pathogenesis of obesity, diabetes, and related metabolic and cardiovascular disorders [2,5]. There is also evidence indicating that increased levels of CRP may not only reflect the presence of inflammation, but also may promote inflammation and the risk for features of the metabolic syndrome and diabetes [3,6,7]. Therefore, in the current study in an animal model with inflammatory and metabolic disturbances induced by transgenic expression of human CRP, we tested the anti-inflammatory, antioxidative, and metabolic effects of Fumaderm, a preparation of fumaric acid esters containing DMF.…”

“…Recently, we derived a new strain of ''humanized'' spontaneously hypertensive rats (SHR-CRP) in which transgenic expression of human C-reactive protein (CRP) in liver induces inflammation, oxidative stress, several features of metabolic syndrome, and target organ damage [3]. In the current study, we explored whether FAE can exert anti-inflammatory and anti-oxidative actions associated with metabolic effects in this animal model.…”

CRP induces hypertension in animal models: homo sapiens says NO

“…Recently, Pravanec et al 7 reported that in spontaneously hypertensive rats, human CRP under the control of the apolipoprotein E promoter resulted in a substantial increase in human CRP levels. This increase in CRP resulted in an increase in both systolic and diastolic BPs measured by telemetry, compared with the spontaneously hypertensive rat controls.…”

“…It should be emphasized, however, that unlike the current study and the study by Guan et al, 5 they suggested this effect was not attributable to the effect of theAT-1 receptor, which was unaltered, but to a decrease in the AT-2 receptor. However, the study by Vongpatanasin et al 6 provided little further information with regard to molecular insights.Recently, Pravanec et al 7 reported that in spontaneously hypertensive rats, human CRP under the control of the apolipoprotein E promoter resulted in a substantial increase in human CRP levels. This increase in CRP resulted in an increase in both systolic and diastolic BPs measured by telemetry, compared with the spontaneously hypertensive rat controls.…”