Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through C-C Chemokine Receptor Type 2 Downregulation and Enhanced MMP Balance

Abstract

Abstract Abdominal aortic aneurysms (AAAs) are prevelant with aging, and AAA rupture is associated with high mortality. There is currently no effective medical therapy for AAA rupture. Previous work demonstrated that the monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. Here we similarly observed that Ccr2-/- mice have significantly reduced AAA expansion and rupture. We therefore hypothesized that a dietary modulation of the CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we specifically evaluated whether systemic ketosis in vivo can reduce CCR2 and AAA progression. Male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase (PPE), and received daily β-aminopropionitrile (BAPN) to promote AAA rupture. Animals with AAAs received either a standard diet (SD), ketogenic diet (KD), or exogenous KBs (EKB). Animals recieving KD and EKB reached a state of ketosis, and had significant reduction in AAA expansion and incidence of rupture. Ketosis also led to significantly reduced aortic CCR2 content, improved MMP balance, and reduced ECM degradation. In summary, this study demonstrates that ketosis plays a crucial role in AAA pathobiology, and provides the impetus for future clinical studies investigating the potential benefit of ketosis for prevention of AAA expansion and rupture.