Abstract 394: Angiotensin II Mediated Increase in Hypertension and Cardiac Hypertrophy in MyD88 Knockout Mice

Abstract

Toll-like receptors (TLR) are a class of pattern-recognizing receptors (PRR) that play a central role in the innate immune response during infection and sterile injury. MyD88 is an adapter protein that mediates the majority of TLR responses. Since inflammation is a coexisting condition in several cardiovascular diseases, TLRs are thought to play a major role in these conditions. We have previously shown that indeed post-MI survival was significantly improved and cardiac fibrosis and hypertrophy were reduced in MyD88-/- mice (Singh et al. 2012. JMCC). In this study we tested whether angiotensin II (AngII) hypertension and cardiac hypertrophy depended on TLR signaling pathways mediated by MyD88. Male MyD88-/- mice and C57BL/6 mice of 10 to 12 weeks of age were subcutaneously implanted with osmotic minipumps (Alzet) eluting saline or AngII (Sigma, 733 ng/kg/min). Tailcuff pressures were measured with BP2000 (Visitech Systems). Mice were sacrificed after 3 weeks of AngII infusion and hearts were collected for weighing and gene expression analyses. In control WT mice, mean arterial pressure (MAP) remained near baseline levels during the first week of infusion averaging 71± 2 mm Hg and then increased to an average of 100 ± 3 mm Hg and 102 ± 2 mm Hg during the 2nd and 3rd weeks of infusions, respectively. In MyD88-/- mice, MAP increased from a baseline of 84 ± 3 to a high of 120 ± 7 mm Hg during the first week and then declined to 109 ± 6 and 91 ± 9 mm Hg during the 2nd and 3rd weeks. The heart weight to body weight ratios (HW/BW x 1000) after 3 weeks of AngII infusion were not significantly different between WT (5.23 ± 0.15) and MyD88-/- (4.76 ± 0.16). Increases in cardiac hypertrophic marker gene Acta1 were up 4-fold in both WT and MyD88-/- mice, and increases in proinflammatory TNF-alpha, IL-1β, and Nox4 were seen in both genotypes, but the increase in TNF-alpha was significantly greater in MyD88-/- mice. We conclude that unlike post- MI cardiac hypertrophy, the AngII cardiac hypertrophy is not MyD88 -dependent, yet the delayed Ang II pressor response is abrogated in the absence of MyD88. The delayed pressor response to AngII infusion is likely dependent on the immune system.