Overexpression of human C-reactive protein exacerbatesleft ventricular remodeling in diabetic cardiomyopathy

Background: C-reactive protein (CRP) is known to be a pathogenic agent in the cardiovascular system. However,the effect of CRP on heart failure has not been elucidated. The effect of human CRP on cardiac dysfunctioninduced by diabetes mellitus (DM) using human CRP-overexpressing transgenic mice (CRP-Tg) wasexamined.Methods and Results: DM was induced in male wild-type mice (Wt/DM) and CRP-Tg (CRP/DM) by an injectionof streptozotocin. Non-diabetic wild-type mice (Wt/Con) and CRP-Tg (CRP/Con) served as controls. Echocardiographyand hemodynamic measurements 6 weeks after injection showed lower fractional shortening and leftventricular (LV) dP/dt max in CRP/DM compared with Wt/DM. Myocardial mRNA levels of interleukin-6, tumornecrosis factor-α, plasminogen activator inhibitor-1, angiotensin type 1 receptor, angiotensinogen, NADPH oxidasesubunits (p47 ^phox, gp91 ^phox), glutathione peroxidase-3. and connective tissue growth factor were increased inCRP/DM compared with Wt/DM. Nuclear staining of 8-hydroxydeoxyguanosine was also increased in CRP/DMcompared with Wt/DM. CRP/DM was associated with increased terminal deoxynucleotidyl transferase-mediateddUTP nick end-labeling positive cells and a higher ratio of Bax/Bcl-2 proteins compared with Wt/DM. The extentof cardiac fibrosis assessed by Sirius red staining and immunohistochemical staining for collagen type 1 was significantlyincreased in CRP/DM compared with Wt/DM.Conclusions: Overexpression of human CRP exacerbates LV dysfunction and remodeling in diabetic cardiomyopathy,possibly through enhancement of the inflammation, renin-angiotensin system, and oxidative stress.