Sirt1 overexpression attenuates high-fat diet induced aortic stiffening

Increased arterial stiffness is a cardiovascular disease risk factor in the setting of advancing age and high-fat (HF) diet induced obesity. Increases in large artery stiffness, as measured by pulse wave velocity (PWV), occur within 8 weeks of HF feeding in mice. Sirtuin-1 (Sirt1), a NAD-dependent deacetylase, regulates cellular metabolic activity and activation of this protein has been associated with vasoprotection in aged mice. The aim of the present study was to elucidate the effect of global Sirt1 overexpression (Sirttg) on HF diet-induced arterial stiffening. Sirt1 overexpression did not influence PWV in normal chow (NC) fed mice (Sirttg: 263 {+/-} 6 vs WT: 274 {+/-} 7, p=0.28). However, PWV was higher in wild-type (WT) mice (376 {+/-} 22, p<0.04), but not Sirttg (304 {+/-} 2 cm/s, p=0.07), after 12 weeks of HF diet. Despite no effect of Sirt1 overexpression on aortic collagen content in NC (p=0.71), aortic elastin content was higher in Sirttg mice compared with WT mice fed NC diet (P<0.05). Surprisingly, despite increased arterial stiffness, collagen content was lower (p<0.02) and elastin content was unchanged (p=0.05) in the aortas of WT mice after HF. Neither collagen (p=0.18) nor elastin content (p=0.56) were impacted by HF diet in the Sirttg mice. Likewise, there was no difference in wall thickness in NC (Sirttg: 40.7 {+/-} 2 vs WT: 41.6 {+/-} 2, p= 0.78). However, wall thickness was higher in mice WT mice fed a HF diet (51.7 {+/-} 2, p<0.01) and there was no difference in Sirttg mice after HF diet (p=0.66). Similarly, there was no difference in wall-to-lumen ratio in mice fed NC diet (Sirttg: 0.08 vs WT: 0.08, p=0.48) was higher in HF diet fed WT mice (p<0.01), though, HF diet was associated with a higher wall-to-lumen ratio in WT (0.11, p<0.01), but not different in Sirttg mice fed HF diet (0.08, p=0.59). These findings demonstrate a vasoprotective effect of Sirt1 overexpression that limits increases in arterial stiffness and protects against alterations in vessel morphology in response to HF feeding. As such, activation of Sirt1 may be a novel therapeutic target to prevent elevated CVD risk associated with HF-induced aortic stiffening.