TY - JOUR
T1 - Nuclear-mitochondrial communication involving miR-181c plays an important role in cardiac dysfunction during obesity
AU - Roman, Barbara
AU - Kaur, Pawandeep
AU - Ashok, Deepthi
AU - Kohr, Mark
AU - Biswas, Roopa
AU - O'Rourke, Brian
AU - Steenbergen, Charles
AU - Das, Samarjit
N1 - Funding Information:
We thank John Elrod of the Center for Translational Medicine in the Lewis Katz School of Medicine at Temple University for providing the MCUflox/flox mice for the study. None. This work was supported by American Heart Association grants 14SDG18890049, MSCRF, and Mscrfd-4313 and a Stimulating and Advancing ACCM Research (StAAR) grant from the Johns Hopkins University Department of Anesthesiology and Critical Care Medicine (to S.D.), and by National Institutes of Health grants 5R01HL039752 (to C.S.), R01HL137259 (to B.O'R.), and R01HL136496 (to M.K.).
Funding Information:
This work was supported by American Heart Association grants 14SDG18890049, MSCRF, and Mscrfd-4313 and a Stimulating and Advancing ACCM Research (StAAR) grant from the Johns Hopkins University Department of Anesthesiology and Critical Care Medicine (to S.D.), and by National Institutes of Health grants 5R01HL039752 (to C.S.), R01HL137259 (to B.O'R.), and R01HL136496 (to M.K.).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/7
Y1 - 2020/7
N2 - Aims: In cardiomyocytes, there is microRNA (miR) in the mitochondria that originates from the nuclear genome and matures in the cytoplasm before translocating into the mitochondria. Overexpression of one such miR, miR-181c, can lead to heart failure by stimulating reactive oxygen species (ROS) production and increasing mitochondrial calcium level ([Ca2+]m). Mitochondrial calcium uptake 1 protein (MICU1), a regulatory protein in the mitochondrial calcium uniporter complex, plays an important role in regulating [Ca2+]m. Obesity results in miR-181c overexpression and a decrease in MICU1. We hypothesize that lowering miR-181c would protect against obesity-induced cardiac dysfunction. Methods and results: We used an in vivo mouse model of high-fat diet (HFD) for 18 weeks and induced high lipid load in H9c2 cells with oleate-conjugated bovine serum albumin in vitro. We tested the cardioprotective role of lowering miR-181c by using miR-181c/d−/− mice (in vivo) and AntagomiR against miR-181c (in vitro). HFD significantly upregulated heart levels of miR-181c and led to cardiac hypertrophy in wild-type mice, but not in miR-181c/d−/− mice. HFD also increased ROS production and pyruvate dehydrogenase activity (a surrogate for [Ca2+]m), but the increases were alleviated in miR-181c/d−/− mice. Moreover, miR-181c/d−/− mice fed a HFD had higher levels of MICU1 than did wild-type mice fed a HFD, attenuating the rise in [Ca2+]m. Overexpression of miR-181c in neonatal ventricular cardiomyocytes (NMVM) caused increased ROS production, which oxidized transcription factor Sp1 and led to a loss of Sp1, thereby slowing MICU1 transcription. Hence, miR-181c increases [Ca2+]m through Sp1 oxidation and downregulation of MICU1, suggesting that the cardioprotective effect of miR-181c/d−/− results from inhibition of Sp1 oxidation. Conclusion: This study has identified a unique nuclear-mitochondrial communication mechanism in the heart orchestrated by miR-181c. Obesity-induced overexpression of miR-181c increases [Ca2+]m via downregulation of MICU1 and leads to cardiac injury. A strategy to inhibit miR-181c in cardiomyocytes can preserve cardiac function during obesity by improving mitochondrial function. Altering miR-181c expression may provide a pharmacologic approach to improve cardiomyopathy in individuals with obesity/type 2 diabetes.
AB - Aims: In cardiomyocytes, there is microRNA (miR) in the mitochondria that originates from the nuclear genome and matures in the cytoplasm before translocating into the mitochondria. Overexpression of one such miR, miR-181c, can lead to heart failure by stimulating reactive oxygen species (ROS) production and increasing mitochondrial calcium level ([Ca2+]m). Mitochondrial calcium uptake 1 protein (MICU1), a regulatory protein in the mitochondrial calcium uniporter complex, plays an important role in regulating [Ca2+]m. Obesity results in miR-181c overexpression and a decrease in MICU1. We hypothesize that lowering miR-181c would protect against obesity-induced cardiac dysfunction. Methods and results: We used an in vivo mouse model of high-fat diet (HFD) for 18 weeks and induced high lipid load in H9c2 cells with oleate-conjugated bovine serum albumin in vitro. We tested the cardioprotective role of lowering miR-181c by using miR-181c/d−/− mice (in vivo) and AntagomiR against miR-181c (in vitro). HFD significantly upregulated heart levels of miR-181c and led to cardiac hypertrophy in wild-type mice, but not in miR-181c/d−/− mice. HFD also increased ROS production and pyruvate dehydrogenase activity (a surrogate for [Ca2+]m), but the increases were alleviated in miR-181c/d−/− mice. Moreover, miR-181c/d−/− mice fed a HFD had higher levels of MICU1 than did wild-type mice fed a HFD, attenuating the rise in [Ca2+]m. Overexpression of miR-181c in neonatal ventricular cardiomyocytes (NMVM) caused increased ROS production, which oxidized transcription factor Sp1 and led to a loss of Sp1, thereby slowing MICU1 transcription. Hence, miR-181c increases [Ca2+]m through Sp1 oxidation and downregulation of MICU1, suggesting that the cardioprotective effect of miR-181c/d−/− results from inhibition of Sp1 oxidation. Conclusion: This study has identified a unique nuclear-mitochondrial communication mechanism in the heart orchestrated by miR-181c. Obesity-induced overexpression of miR-181c increases [Ca2+]m via downregulation of MICU1 and leads to cardiac injury. A strategy to inhibit miR-181c in cardiomyocytes can preserve cardiac function during obesity by improving mitochondrial function. Altering miR-181c expression may provide a pharmacologic approach to improve cardiomyopathy in individuals with obesity/type 2 diabetes.
KW - MICU1
KW - Mitochondria
KW - Mitochondrial calcium
KW - Obesity
KW - miR-181c
KW - microRNA
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U2 - 10.1016/j.yjmcc.2020.05.009
DO - 10.1016/j.yjmcc.2020.05.009
M3 - Article
C2 - 32442661
AN - SCOPUS:85085283643
VL - 144
SP - 87
EP - 96
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -