title: Macrophages dictate the progression and manifestation of hypertensive heart disease.
abstract: BACKGROUND
  Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling.
  
  
  RESULTS
  We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p<0.05), and reduced cardiac fibrosis by 75%, compared with controls (p=0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p<0.05), and a 13% in LV mass (p=0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p=0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%).
  
  
  CONCLUSIONS
  Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Kain
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Amit
authors.affiliation: Laboratory for Molecular Medicine and Israeli Rat Genome Center, Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon, Israel.
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landa
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel.
authors.forename: Nili
authors.initials: N
authors.lastname: Naftali-Shani
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel.
authors.forename: Natali
authors.initials: N
authors.lastname: Molotski
authors.affiliation: Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Aviv
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Micha S
authors.initials: MS
authors.lastname: Feinberg
authors.affiliation: Diagnostic Imaging Department, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Goitein
authors.affiliation: Diagnostic Imaging Department, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Tammar
authors.initials: T
authors.lastname: Kushnir
authors.affiliation: Diagnostic Imaging Department, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Konen
authors.affiliation: University of Virginia, Department of Biomedical Engineering, Charlottesville, VA, USA.
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Epstein
authors.affiliation: Laboratory for Molecular Medicine and Israeli Rat Genome Center, Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.affiliation: Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel-Hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel. Electronic address: leorj@post.tau.ac.il.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leor
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D018450:Disease Progression; D017379:Hypertrophy, Left Ventricular / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
keywords: Fibrosis; Heart; Hypertension; Hypertrophy; Macrophage; Remodeling