title: Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications.
abstract: Growing body of evidence points out the crucial role of ACE2 in preventing atherosclerosis. However, data on how atherosclerosis affects ACE2 expression in heart and kidney remains unknown. Atherosclerosis was induced by feeding New Zealand White rabbits with high cholesterol diet (HCD - 2%) for 12 weeks and atorvastatin was administered (5mg/kg/day p.o) in last 3 weeks. ACE2 mRNA and protein expression was assessed by Western blotting and real time PCR. HCD fed rabbits developed atherosclerosis as confirmed by increase in plasma total cholesterol, LDL and triglycerides as well as formation atherosclerotic plaques in arch of aorta. The ACE2 protein but not mRNA expression was reduced in heart and kidney of HCD rabbits. Interestingly, atorvastatin increased the ACE2 protein expression in heart and kidney of HCD rabbits. However, atorvastatin increased ACE2 mRNA in heart but not in kidney of HCD rabbits. Atorvastatin increased the occupancy of histone H3 acetylation (H3-Ac) mark on ACE2 promoter region in heart of HCD rabbits indicating direct or indirect epigenetic up-regulation of ACE2 by atorvastatin. Further, atorvastatin suppressed Ang II-induced contractile responses and enhanced AT2 receptor mediated relaxant responses in atherosclerotic aorta. We propose that atherosclerosis is associated with reduced ACE2 expression in heart and kidney. We also show an unexplored potential of atorvastatin to up-regulate ACE2 via epigenetic histone modifications. Our data suggest a novel way of replenishing ACE2 expression for preventing not only atherosclerosis but also other cardiovascular disorders.
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India. Electronic address: tikoo.k@gmail.com.
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Tikoo
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India.
authors.forename: Gaurang
authors.initials: G
authors.lastname: Patel
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India.
authors.forename: Pinakin Arun
authors.initials: PA
authors.lastname: Karpe
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India.
authors.forename: Maitri
authors.initials: M
authors.lastname: Sanghavi
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India.
authors.forename: Vajir
authors.initials: V
authors.lastname: Malek
authors.affiliation: Laboratory of Epigenetics and Disease, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab-160062, India.
authors.forename: K
authors.initials: K
authors.lastname: Srinivasan
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000069059:Atorvastatin; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000502:physiology; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006657:Histones / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D006538:Heptanoic Acids; D006657:Histones; D011758:Pyrroles; D000069059:Atorvastatin; D007703:Peptidyl-Dipeptidase A; D000085962:Angiotensin-Converting Enzyme 2
keywords: ACE2; Angiotensin II; Atherosclerosis; Atorvastatin; Histone H3 acetylation; Losartan; PD123319; Phenylephrine and cholesterol