OBJECTIVE: Chronic ischemia is associated with alterations in genes that result in myocardial remodeling. An important biochemical basis of cardiac remodeling is generation of reactive oxygen species (ROS). A few studies have suggested that acute ischemia triggers signals for remodeling. We examined the hypothesis that targeted deletion of lectin-like oxidized-LDL receptor (LOX-1) may inhibit signals related to cardiac remodeling. METHODS AND RESULTS: We generated LOX-1 knockout (KO) mice on C57BL/6 (wild-type mice) background, and subjected wild-type and KO mice to ischemia-reperfusion (I-R). The wild-type mice developed a marked reduction in left ventricular systolic pressure and +/-dp/dt(max) and an increase in left ventricular end-diastolic pressure following I-R, and this change was much less in the LOX-1 KO mice, indicating preservation of left ventricular function with LOX-1 deletion. There was evidence for marked oxidative stress (NADPH oxidase expression, malondialdehyde and 8-isoprostane) following I-R in the wild-type mice, much less so in the LOX-1 KO mice (P<0.01). In concert, collagen deposition (Masson's trichrome and Picro-sirius red staining) increased dramatically in the wild-type mice, but only half as much in the LOX-1 KO mice (P<0.01). Collagen staining data was corroborated with procollagen-I expression. Further, fibronectin and osteopontin expression increased in the wild-type mice, but to a much smaller extent in the LOX-1 KO mice (P<0.01). CONCLUSIONS: These findings provide compelling evidence that LOX-1 is a key modulator of cardiac remodeling which starts immediately following I-R.
OBJECTIVE:Chronic ischemia is associated with alterations in genes that result in myocardial remodeling. An important biochemical basis of cardiac remodeling is generation of reactive oxygen species (ROS). A few studies have suggested that acute ischemia triggers signals for remodeling. We examined the hypothesis that targeted deletion of lectin-like oxidized-LDL receptor (LOX-1) may inhibit signals related to cardiac remodeling. METHODS AND RESULTS: We generated LOX-1 knockout (KO) mice on C57BL/6 (wild-type mice) background, and subjected wild-type and KO mice to ischemia-reperfusion (I-R). The wild-type mice developed a marked reduction in left ventricular systolic pressure and +/-dp/dt(max) and an increase in left ventricular end-diastolic pressure following I-R, and this change was much less in the LOX-1 KO mice, indicating preservation of left ventricular function with LOX-1 deletion. There was evidence for marked oxidative stress (NADPH oxidase expression, malondialdehyde and 8-isoprostane) following I-R in the wild-type mice, much less so in the LOX-1 KO mice (P<0.01). In concert, collagen deposition (Masson's trichrome and Picro-sirius red staining) increased dramatically in the wild-type mice, but only half as much in the LOX-1 KO mice (P<0.01). Collagen staining data was corroborated with procollagen-I expression. Further, fibronectin and osteopontin expression increased in the wild-type mice, but to a much smaller extent in the LOX-1 KO mice (P<0.01). CONCLUSIONS: These findings provide compelling evidence that LOX-1 is a key modulator of cardiac remodeling which starts immediately following I-R.
Authors: Izma Abdul Zani; Sam L Stephen; Nadeem A Mughal; David Russell; Shervanthi Homer-Vanniasinkam; Stephen B Wheatcroft; Sreenivasan Ponnambalam Journal: Cells Date: 2015-05-22 Impact factor: 6.600