Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Abstract

Objective-One potential mechanism through which obesity exerts adverse effects on the vascular system is by increasing aortic stiffness, a change known to be predictive of increased cardiovascular mortality. The aim of this study was to investigate the pathophysiology that links obesity to aortic stiffening. Approach and Results-Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans. Conclusion-Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity.

Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice

“…The finding for increased IL-6 secretion from PVAT is consistent with previous observations for greater inflammatory cytokine secretion and expression, including IL-6, from PVAT of old and high-fat diet-fed mice (2,11,16). Importantly, these findings were extended to provide direct evidence for PVATderived IL-6 to increase aortic stiffening of arteries from LDLr Ϫ/Ϫ mice.…”

Diabetes increases stiffness of live cardiomyocytes measured by atomic force microscopy nanoindentation

“…The effect of aging and obesity on vascular smooth muscle cell stiffness (8,21,38) and the effect of aging on cardiomyocyte stiffness (15) were analyzed using AFM. Cell thickness is an important factor in determining AEM.…”

“…Different cell events, such as locomotion, differentiation and aging, physiological activation, electromotility, and cell pathology, can be analyzed with this new research tool (8,13,15,17,21,37,38). The effects of aging and obesity on vascular smooth muscle cell stiffness (8,21,38) and aging on cardiomyocyte stiffness (15) have been analyzed using AFM. However, to our knowledge, no studies have examined directly the effect of diabetes on the material properties of single live cardiomyocytes.…”

Arterial stiffness is associated with adipokine dysregulation in non-hypertensive obese mice

“…Total wall CSA was significantly higher after 32-wk of HFD compared to control diet (1-ANOVA, F (1,15) =7.318, p<0.05; Figure 3A). These differences were due to a significant increase in both the adventitial CSA (1-ANOVA, F (1,16) =4.457; p<0.05) and the medial CSA (1-ANOVA, F (1,14) =5.216; p<0.05). Total number of adventitial and smooth muscle cells (SMC) were significantly increased in HFD compared with the control group ( Figure 3B; p<0.05).…”

“…Obesity is associated with an increase in aortic pulse wave velocity (PWV) and/or intrinsic stiffness (assessed by the stress-strain relationship) in human subcutaneous small resistance arteries 6,[11][12][13] , as well as in aorta of high-fat/high-sucrose SD 7 or in genetic models of obesity, i.e. ob/ob mice 14 and insulinresistant Zucker fa/fa rats 8 . Recent evidence suggests that arterial stiffness associated to obesity might appear in the absence or prior to the development of hypertension in patients with metabolic syndrome 13 .…”