Sirt3 Protects Against Thoracic Aortic Dissection Formation by Reducing Reactive Oxygen Species, Vascular Inflammation, and Apoptosis of Smooth Muscle Cells

Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. Here, we have shown that Sirt3 protects the mouse heart by blocking the cardiac hypertrophic response. Although Sirt3-deficient mice appeared to have normal activity, they showed signs of cardiac hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced a severe cardiac hypertrophic response, whereas Sirt3-expressing Tg mice were protected from similar stimuli. In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a-dependent (Foxo3a-dependent), antioxidant-encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. Reduced ROS levels suppressed Ras activation and downstream signaling through the MAPK/ERK and PI3K/Akt pathways. This resulted in repressed activity of transcription factors, specifically GATA4 and NFAT, and translation factors, specifically eukaryotic initiation factor 4E (elf4E) and S6 ribosomal protein (S6P), which are involved in the development of cardiac hypertrophy. These results demonstrate that SIRT3 is an endogenous negative regulator of cardiac hypertrophy, which protects hearts by suppressing cellular levels of ROS.

The role of inflammation in the pathogenesis of abdominal aortic aneurysms (AAA) is well established. The inflammatory process leads to protease-mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells (SMC), which are the predominant matrix synthesizing cells of the vascular wall. These processes act in concert to progressively weaken the aortic wall, resulting in dilatation and aneurysm formation. Oxidative stress is invariably increased in, and contributes importantly to, the pathophysiology of inflammation. Moreover, reactive oxygen species (ROS) play a key role in regulation of matrix metalloproteinases and induction of SMC apoptosis. ROS may also contribute to the pathogenesis of hypertension, a risk factor for AAA. Emerging evidence suggests that ROS and reactive nitrogen species (RNS) are associated with AAA formation in animal models and in humans. Although experimental data are limited, several studies suggest that modulation of ROS production or activity may suppress AAA formation and improve experimental outcome in rodent models. Although a number of enzymes can produce injurious ROS in the vasculature, increasing evidence points toward a role for NADPH oxidase as a source of oxidative stress in the pathogenesis of AAA.

Smoking is the only modifiable risk factor that is associated with the development, expansion and rupture of abdominal aortic aneurysm (AAA). However, the causative link between cigarette smoke and AAA is unknown. Here we report a causative link between smoking and AAA in vivo. Acute infusion of angiotensin II (AngII) or nicotine, a major component of cigarette smoke, markedly increased the incidence of AAA in apolipoprotein E (apoE) knockout (Apoe(-/-)) mice and in mice deficient in both apoE and the AMP-activated kinase α1 subunit (AMPK-α1) (Apoe(-/-); Prkaa1(-/-) mice). In contrast, genetic deletion of AMPK-α2 (Apoe(-/-); Prkaa2(-/-) mice) ablated nicotine- or AngII-triggered AAA in vivo. Mechanistically, we found that both nicotine and AngII activated AMPK-α2 in cultured vascular smooth muscle cells (VSMCs), resulting in the phosphorylation of activator protein 2α (AP-2α) and consequent matrix metallopeptidase 2 (MMP2) gene expression. We conclude that smoking (through nicotine) instigates AAA through AMPK-α2–mediated AP-2α–dependent MMP2 expression in VSMCs.