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Background and Objective: Arterial stiffness is recognized as being an independent predictor of incipient vascular disease associated with obesity and metabolic syndrome. In obese subjects, the decrease in the plasma level of adiponectin, an anti-diabetic and anti-atherogenic adipokine, is well known. Hence the aim of our study was to examine the effect of loss of adiponectin on the development of arterial stiffness in response to a high fat diet. Methods and Results: Male 8-week old adiponectin knockout (APN KO) and C57BL/6 (control) mice were fed a high fat diet (60% Calories from fat) for 12 weeks to induce obesity and insulin resistance (n=10/group). APN KO and C57BL/6 mice were fed a low fat diet (10% Calories from fat) and used as lean controls (n=10/group). After 12 weeks on the high fat diet, the APN KO mice weighed significantly more than the C57BL/6 mice (45.1±1.3 g vs 40.1±1.1 g, p=0.0008) but there was no difference in the final weights between genotypes fed the low fat diet. APN KO mice on both high and low fat diets for 12 weeks developed insulin resistance as measured by oral glucose tolerance test (Area under curve (AUC) mmol/L х min = 437±70 and 438±57) as compared to the C57BL/6 mice fed low or high fat diets (AUC mmol/L х min = 251±27 and 245±43). Arterial stiffness was determined by Doppler pulse wave velocity analysis of the femoral artery. Pulse wave velocity was increased in APN KO mice fed a high fat diet relative to those fed the low fat diet (12.56±0.78 cm/s vs 9.47±0.95 cm/s, p=0.0035; n=8-10). Pulse wave velocity was not different between C57BL/6 control mice on the low or high fat diets (10.63±0.73 cm/s and 10.86±0.50 cm/s), thus revealing that only mice deficient in adiponectin developed arterial stiffness in response to high fat diet. Conclusions: Potentiation of the vascular stiffness in diet-induced obese APN KO mice indicates that adiponectin has a role in modulating vascular structure and the APN KO mouse models the vascular changes that occur in human obesity and metabolic disorders. Morphometric analysis of the aortic tissues for vessel thickness and expression of extracellular proteins will further validate the potential role of adiponectin on the maintenance of arterial elasticity in addition to its known effect on eNOS mediated vasoprotection.

Cardiac hypertrophy is the compensatory enlargement of the heart aimed at reducing stress induced by either pressure overload or volume overload (VO); however, sustained hypertrophy leads to cardiac dysfunction. We hypothesize that cardiac dysfunction which develops due to VO will be associated with abnormalities in sarcoplasmic reticulum (SR) function. Volume overload was induced in rats by aortocaval shunt surgery ('VO rats'). Echocardiographic measurements were used to compare cardiac structure and function in control and VO rats. The SR was isolated from left ventricular tissue. Sarcoplasmic reticulum Ca(2+) uptake and SR Ca(2+) release were examined by the filtration method. The expression levels of SR proteins were assessed by Western immunoblotting. Rats subjected to VO developed eccentric hypertrophy. Diastolic function in VO rats was improved at all time points and was associated with elevated SR Ca(2+) uptake at 16 and 28 weeks. Sarcoendoplasmic reticulum ATPase 2a protein level was increased at 16 weeks but normalized at 28 weeks; Amounts of phospholamban protein were unaltered, but Serine16 phospholamban and Threonine17 phospholamban were reduced at 28 weeks. Systolic function was impaired in the VO rats at 16 and 28 weeks and was associated with reduced Ca(2+) release at the 28 week time point. The ryanodine receptor 2 (RyR2) protein level was reduced at 28 weeks; RyR2 phosphorylation status and the amount of FK-binding protein 12.6 were increased at 28 weeks. On the basis of the results, we conclude that the progression of hypertrophy due to VO in rats is accompanied by the impairment of systolic function, which in turn is associated with defects in RyR2 expression and function.