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- W4232737521 abstract "Rationale/Objective: Cardiac hypertrophy is associated with a metabolic switch in substrate utilization from fatty acids to glucose. Levels of Hexokinase II (HKII), a key regulator of glucose metabolism, increase in response to hypertrophic stimulation and we hypothesized that a reduction in HKII could attenuate the hypertrophic response. Methods/Results : Contrary to our hypothesis, heterozygous knockout of HKII (HKII+/-) resulted in exaggerated cardiac hypertrophy after the induction of pressure overload by trans-aortic constriction (TAC). HKII+/- mice demonstrated increased heart size, interstitial fibrosis, and pulmonary edema compared to wild-type (WT) 4 weeks after TAC. This was associated with reduced cardiac function and increased mortality in the HKII+/- mice by the 8-week time point, indicating an accelerated transition to heart failure. In primary cultures of neonatal rat cardiomyocytes (NRCM), siRNA knockdown of HKII exacerbated the hypertrophic response to Angiotensin II (AngII) compared to control siRNA. Mechanistically, reduction of HKII resulted in increased ROS levels after hypertrophic stimulation relative to controls. Treatment of NRCM with the antioxidant N -acetylcysteine (NAC) attenuated the hypertrophic response to AngII, and abrogated the increased hypertrophy observed with HKII knockdown. In addition to its enzymatic activity, HKII can bind the outer membrane of the mitochondria, and this interaction increased with hypertrophic agonists. Dissociation of HKII from the mitochondria using a synthetic cell permeable peptide resulted in de novo hypertrophy compared with scrambled peptide control, and this was also attenuated with NAC treatment. Further investigation into the source of ROS revealed that HKII knockdown (+AngII) or mitochondrial dissociation resulted in increased mitochondrial permeability pore (mPTP) opening in the absence of cell death. Conclusions: Overall, the data suggest that HKII and its binding to the mitochondria serve as a negative regulator of hypertrophy by decreasing ROS production, possibly through regulation of the mPTP." @default.
- W4232737521 created "2022-05-12" @default.
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- W4232737521 date "2011-12-09" @default.
- W4232737521 modified "2023-09-27" @default.
- W4232737521 title "Abstract P214: Reduction of Hexokinase II Exaggerated Cardiac Hypertrophy via Increased ROS Production and Mitochondrial Permeability Transition" @default.
- W4232737521 doi "https://doi.org/10.1161/res.109.suppl_1.ap214" @default.
- W4232737521 hasPublicationYear "2011" @default.
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