Protective Effect of RA on Myocardial Infarction-Induced Cardiac Fibrosis via AT1R/p38 MAPK Pathway Signaling and Modulation of the ACE2/ACE Ratio

J Agric Food Chem. 2016 Sep 7;64(35):6716-22. doi: 10.1021/acs.jafc.6b03001. Epub 2016 Aug 29.


Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid, RA) is a major active constituent of Rosmarinus officinalis Linn. (rosemary) having significant anti-inflammatory, anti-apoptotic, and antioxidant effects. However, the cardioprotection of RA is still not understood. The present study was designed, for the first time, to investigate the cardioprotection of RA on myocardial infarction (MI)-induced cardiac fibrosis and to clarify the possible mechanisms. MI was induced in adult rats by left anterior descending coronary artery ligation, and animals were then administered RA (50, 100, or 200 mg/kg) by gavage. Compared with the model group, RA treatment ameliorated changes in the left ventricular systolic pressure (LVSP), +dp/dtmax, and -dp/dtmax after 4 weeks. This was associated with attenuation of infarct size, collagen volume fraction (CVF), expression of collagen I, collagen III, alpha smooth muscle actin (α-SMA), and hydroxyproline (Hyp) concentrations. RA treatment was also associated with decreased angiotensin-converting enzyme (ACE) expression and increased ACE2 expression, as well as decreased expression of angiotensin type 1 receptor (AT1R) and phospho-p38 mitogen-activated protein kinase (p38 MAPK). Thus, RA can protect against cardiac dysfunction and fibrosis following MI, likely due to decreasing ACE expression and increasing ACE2 expression via the AT1R/p38 MAPK pathway.

Keywords: ACE; ACE2; AT1R/p38 MAPK; RA; cardiac dysfunction; cardiac fibrosis.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Blood Pressure / drug effects
  • Cinnamates / administration & dosage*
  • Depsides / administration & dosage*
  • Fibrosis / etiology
  • Fibrosis / genetics
  • Fibrosis / metabolism
  • Fibrosis / prevention & control*
  • Heart / drug effects*
  • Heart / physiopathology
  • Humans
  • Male
  • Myocardial Infarction / complications*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Peptidyl-Dipeptidase A / metabolism
  • Plant Extracts / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Rosmarinus / chemistry*
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cinnamates
  • Depsides
  • Plant Extracts
  • Receptor, Angiotensin, Type 1
  • p38 Mitogen-Activated Protein Kinases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, rat
  • Angiotensin-Converting Enzyme 2
  • rosmarinic acid