Circadian mutant mice with obesity and metabolic syndrome are resilient to cardiovascular disease

Abstract

Obesity and metabolic syndrome commonly underlie cardiovascular disease. Clock^Δ19/Δ19 mice fed a normal diet develop obesity and metabolic syndrome; however, it is not known whether they develop or are resilient to cardiovascular disease. We found that Clock^Δ19/Δ19 mice do not develop cardiac dysfunction, despite their underlying conditions. Moreover, in contrast to wild-type controls fed a high-fat diet (HFD), Clock^Δ19/Δ19 HFD mice still do not develop cardiovascular disease. Indeed, Clock^Δ19/Δ19 HFD mice have preserved heart weight despite their obesity, no cardiomyocyte hypertrophy, and preserved heart structure and function, even after 24 wk of a HFD. To determine why Clock^Δ19/Δ19 mice are resilient to cardiac dysfunction despite their underlying obesity and metabolic conditions, we examined global cardiac gene expression profiles by microarray and bioinformatics analyses, revealing that oxidative stress pathways were involved. We examined the pathways in further detail and found that 1) SIRT-dependent oxidative stress pathways were not directly involved in resilience; 2) 4-hydroxynonenal (4-HNE) increased in wild-type HFD but not Clock^Δ19/Δ19 mice, suggesting less reactive oxygen species in Clock^Δ19/Δ19 mice; 3) cardiac catalase (CAT) and glutathione peroxidase (GPx) increased, suggesting strong antioxidant defenses in the hearts of Clock^Δ19/Δ19 mice; and 4) Pparγ was upregulated in the hearts of Clock^Δ19/Δ19 mice; this circadian-regulated gene drives transcription of CAT and GPx, providing a molecular basis for resilience in the Clock^Δ19/Δ19 mice. These findings shed new light on the circadian regulation of oxidative stress and demonstrate an important role for the circadian mechanism in resilience to cardiovascular disease.NEW & NOTEWORTHY We examined whether obesity and metabolic syndrome underlie the development of cardiac dysfunction in circadian mutant Clock^Δ19/Δ19 mice. Surprisingly, we demonstrate that although Clock^Δ19/Δ19 mice develop metabolic dysfunction, they are protected from cardiac hypertrophy, left ventricular remodeling, and diastolic dysfunction, in contrast to wild-type controls, even when challenged with a chronic high-fat diet. These findings shed new light on the circadian regulation of oxidative stress pathways, which can mediate resilience to cardiovascular disease.

Keywords: cardiovascular; circadian; high-fat diet; obesity; oxidative stress; resilience.