Metaflammation in cardiovascular disease

Inflammation is an important mediator in cardiovascular disorders (CVD), but several questions remain unresolved. The mechanisms for the activation of the inflammatory pathways and the balance between resolving and non-resolving mediators need to be better understood. Like the response to microbes, metabolic stress seems also to trigger inflammation. This interaction between metabolic disturbances and inflammation, or metabolic triggered inflammation, has been studied in obesity-related disorders, but its role in atherosclerosis and cardiac disorders is unclear. How metabolic stress activates inflammation and how to attenuate these processes is also incompletely understood. Our hypothesis is that metaflammation plays an important pathogenic role in CVD. We will address the role of metaflammation in atherosclerosis and metabolic cardiomyopathy, two important CVD with overlapping but also distinct pathophysiology. Our results show: (i) NLRP3 inflammasome (an intracellular inflammatory factory) mediates harmful effects on the myocardium when exposed to palmitate or saturated fatty acids; (ii) The NLRP3 inflammasome contributes to pancreatic inflammation and impaired insulin secretion. (iii) We have shown that these NLRP3 inflammasomes also attenuate development of obesity, liver steatosis, hyperlipidemia and myocardial dysfunction during long-time exposure to a high fat diet in an experimental mouse model. (iv) Nicotinamide Phosphoribosyl Transferase (NAMPT, an enzyme of major importance in cellular metabolism) is important for the development of atherosclerosis at least partly through regulation of inflammation. (v) We have shown that by inhibiting NAMPT, the inflammatory responses in monocytes, a crucial cell in the pathogenesis of atherosclerosis, is attenuated at least partly through inhibiting TLR4 signaling. (vi) The DNA repair enzyme NEIL3 regulates fat metabolism and macrophage inflammation in mice that develop atherosclerosis, during high fat diet. Neil3 is also regulated during human atherosclerosis. (vii) We have shown mediator that could resolve inflammation, derived from polyunsaturated fatty acid, are markedly up-regulated in the early phase of myocardial infarction.

1. Vi har etablert NAMT/NAD/sirtuin systemet som en viktig link mellom metabolisme og inflammasjon. 2. Vi har etablert NLRP3 inflammasomet som en viktig link mellom metabolisme og inflammasjon. 3. Vi har påvist en overraskende og ikke tidligere erkjent regulering av «pro-resolving» lipid metabolitter under akutt hjerteinfarkt. 4. Vi har som de første vist DNA reparasjonsenzymer kan være en «missing link» mellom lipider og inflammasjon med epigenetiske modifikasjoner som en mulig mekanisme. 5. Alle disse systemene inneholder viktige angrepspunkter for nye terapi. 6. Prosjektet har også medført at områdene omtalt i 1-4 har blitt viktige/langsiktige satsningsområder for vår forskning med etablering av nye metoder og samarbeidspartnere både nasjonalt og internasjonalt som en viktig konskvens.

Inflammation is an important mediator in cardiovascular disorders (CVD), but several questions remain unresolved. The mechanisms for the activation of the inflammatory pathways and the balance between resolving and non-resolving mediators need to be better understood. Like the response to microbes, metabolic stress seems also to trigger inflammation. This interaction between metabolic disturbances and inflammation, or metabolic triggered inflammation, has been studied in obesity-related disorders, but its role in atherosclerosis and cardiac disorders is unclear. How metabolic stress activates inflammation and how to attenuate these processes is also incompletely understood. Our hypothesis is that metaflammation plays an important pathogenic role in CVD. We will address the role of metaflammation in atherosclerosis and metabolic cardiomyopathy, two important CVD with overlapping but also distinct pathophysiology. Our results so far show: (i) NLRP3 inflammasome (an intracellular inflammatory factory) mediates harmful effects on the myocardium when exposed to palmitate or saturated fatty acids or high fat diet; (ii) The NLRP3 inflammasome contributes to pancreatic inflammation and impaired insulin secretion. (iii) Nicotinamide Phosphoribosyl Transferase (NAMPT, an enzyme of major importance in cellular metabolism) is important for the development of atherosclerosis at least partly through regulation of inflammation. (iv) The DNA repair enzyme NEIL3 regulates fat metabolism and macrophage inflammation in mice that develop atherosclerosis, during high fat but not during normal diet. Neil3 is also regulated during human atherosclerosis. The project will study new pathogenic mechanisms in the progression of CVD with the ambition to delineate novel therapeutic targets. CVD is a leading cause of death and loss of productive life years in Norway and worldwide. The development of new therapeutic options will therefore have important consequences for the society.