Macrophages dictate the progression and manifestation of hypertensive heart disease

David Kain, Uri Amit, Chana Yagil, Natalie Landa, Nili Naftali-Shani, Natali Molotski, Vered Aviv, Micha S. Feinberg, Orly Goitein, Tammar Kushnir, Eli Konen, Fredrik H. Epstein, Yoram Yagil, Jonathan Leor

Research output: Contribution to journalArticlepeer-review

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. Methods and 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.

Original languageEnglish
Pages (from-to)381-395
Number of pages15
JournalInternational Journal of Cardiology
Volume203
DOIs
StatePublished - 15 Jan 2016

Keywords

  • Fibrosis
  • Heart
  • Hypertension
  • Hypertrophy
  • Macrophage
  • Remodeling

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