Impaired left ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of N^ɛ‐(carboxymethyl) lysine

Abstract

Myocardial dysfunction in the absence of myocardial ischemia is frequent in patients with diabetes mellitus but the underlying pathomechanism is unclear. We investigated whether accumulation of advanced glycation end products (AGEs) in the diabetic myocardium is related to its functional abnormalities.In 11 male homozygous Zucker diabetic fatty rats (ZDF/Gmi-fa/fa) aged 37 weeks (OBESE) and 11 non-obese, non-diabetic littermates (LEAN), we measured left ventricular function (pressure -volume catheter) and levels of N q -(carboxymethyl)lysine (CML), a prototypical AGE, in serum and the left ventricle (competitive enzyme linked immuno-assay).Overt diabetes mellitus (HbA1c > 9%) was present in all OBESE animals but not in LEAN. Systolic left ventricular function was not different between the groups, but the markers of left ventricular relaxation, dP / dt min and the relaxation constant s, were impaired in OBESE. In parallel, CML levels were increased in serum (273 T 15 vs. 197 T 10 ng/ml, p < 0.05) and in the left ventricle (18.4 T 1.1 vs. 12.5 T 2.0 ng/mg protein, p < 0.05) in OBESE compared to LEAN. There was a linear correlation between s and the left ventricular CML levels (r = 0.65; p < 0.05).We conclude that type 2 diabetes is associated with predominant left ventricular diastolic dysfunction. Myocardial accumulation of advanced glycation end products may contribute to relaxation abnormalities in type 2 diabetes.

Cardiovascular dysfunction in Zucker obese and Zucker diabetic fatty rats: role of hydronephrosis

“…Recent studies have shown that the augmentation index from the LV pressure-volume impedance catheter provides an accurate assessment of vascular impedance (26). The increase in arterial stiffness and abnormal diastolic relaxation in ZDFO rats are consistent with previous reports demonstrating that hyperglycemia-induced dysfunction in calcium handling (18) and increased accumulation of advanced glycation end products (14,25) contribute to increased arterial stiffness in diabetes.…”

“…We did not find any change in cardiac or LV weight, and although an increase in cardiac weight is often reported it is not a uniform finding; indeed, several papers have reported no change in heart weight in young adult obese Zucker/ZDF rats (25), particularly in the absence of insulin treatment (9). Similarly, we found no differences in myocyte size, apoptosis, or LV chamber dimension in either ZO or ZDFO rats; however, the posterior walls of ZDFO rats were thinner than those of control animals.…”

“…Regardless, we feel that the concomitant existence of LV dysfunction, abnormal adrenergic and angiotensin peptide levels, and hydronephrosis in Zucker/ZDF animals is an important finding that has implications for investigators who are using, or intending to use, this genotype for studies involving cardiovascular function and diabetes. Second, the heart rate and mean arterial and LV end-diastolic pressures are lower in both Zucker/ZDF and SD rats than those previously reported (9,25). We are unable to account for these findings, although it is possible that the extended duration spent under 2% isoflurane anesthesia during the echocardiographic measurements and subsequent surgical preparation before measurement of the hemodynamic parameters (up to 1 h in total) may have contributed to the lower pressures.…”

Cannabinoid/agonist WIN 55,212‐2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS

“…These animals begin to develop hyperglycaemia and insulin resistance at approximately 7 weeks of age, and glucose levels typically reach a plateau (more than 300 mg/dL) by 15-16 weeks of age [27,29]. Under our experimental conditions, ZDF rats at 20 weeks of age had readings for body weight and plasma glucose that were similar to those described by other researchers [17, [39][40][41]. In relation to the CB agonist selected, a nonselective CB agonist, WIN, was chosen for a first approach of this study.…”

Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium

“…AGEs have been detected in myocardium in animals with experimental DM and are thought to contribute to the various manifestations of DM that comprise diabetic cardiomyopathy (Berg et al 1999;Schafer et al 2006). These include abnormalities of ion pumps and contractile proteins, abnormal energy metabolism and increased passive stiffness due to the aforementioned effects on collagen (van Heerebeek et al 2008).…”