| Autor: |
Chen X; Comparative Medicine, Pfizer Inc., Cambridge, Massachusetts., Bollinger E; Internal Medicine Research Unit, Pfizer Inc., Cambridge, Massachusetts., Cunio T; Comparative Medicine, Pfizer Inc., Cambridge, Massachusetts., Damilano F; Internal Medicine Research Unit, Pfizer Inc., Cambridge, Massachusetts., Stansfield JC; Early Clinical Development, Pfizer Inc., Cambridge, Massachusetts., Pinkus CA; Internal Medicine Research Unit, Pfizer Inc., Cambridge, Massachusetts., Kreuser S; Comparative Medicine, Pfizer Inc., Cambridge, Massachusetts., Hirenallur-Shanthappa D; Comparative Medicine, Pfizer Inc., Cambridge, Massachusetts., Roth Flach RJ; Internal Medicine Research Unit, Pfizer Inc., Cambridge, Massachusetts. |
| Abstrakt: |
Mouse models are used to model human diseases and perform pharmacological efficacy testing to advance therapies to humans; most of these studies are conducted in room temperature conditions. At room temperature (22°C), mice are cold-stressed and must use brown adipose tissue (BAT) to maintain body temperature. This cold stress increases catecholamine tone to maintain adipocyte lipid release via lipolysis, which will fuel adaptive thermogenesis. Maintaining rodents at thermoneutral temperatures (28°C) ameliorates the need for adaptive thermogenesis, thus reducing catecholamine tone and BAT activity. Cardiovascular tone is also determined by catecholamine levels in rodents, as β-adrenergic stimuli are primary drivers of not only lipolytic but also ionotropic and chronotropic responses. As mice have increased catecholamine tone at room temperature, we investigated how thermoneutral housing conditions would impact cardiometabolic function. Here, we show a rapid and reversible effect of thermoneutrality on both heart rate and blood pressure in chow-fed animals, which was blunted in animals fed a high-fat diet. Animals subjected to transverse aortic constriction displayed compensated hypertrophy at room temperature, whereas animals displayed less hypertrophy and a trend toward worse systolic function at thermoneutrality. Despite these dramatic changes in blood pressure and heart rate at thermoneutral housing conditions, enalapril effectively improved cardiac hypertrophy and gene expression alterations. There were surprisingly few differences in cardiac parameters in high-fat-fed animals at thermoneutrality. Overall, these data suggest that thermoneutral housing may alter some aspects of cardiac remodeling in preclinical mouse models of heart failure. NEW & NOTEWORTHY Thermoneutral housing conditions cause rapid and reversible changes in mouse heart rate and blood pressure. Despite dramatic reductions in heart rate and blood pressure, thermoneutrality reduced the compensatory hypertrophic response in a pressure overload heart failure model compared with room temperature housing, and ACE inhibitors were still efficacious to prevent pressure overload-induced cardiac remodeling. The effects of thermoneutrality on heart rate and blood pressure are abrogated in the context of diet-induced obesity. |
