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

Abstract

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.

Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents

“…Our results demonstrate that the concentration of Ang-(1–7) increases significantly with the administration of foliar extracts, but not with their combination ( Figure 6 a). This finding is in accordance with those published by other authors who used rosmarinic acid and observed an increase in ACE2 expression [ 37 ]. The increase in the concentration of Ang-(1–7) would lessen the concentration of ROS and might protect the heart during the period of ischemia.…”

“…Our results demonstrate that the infarction significantly increases the concentration of Ang II, while treatments with Ro and Co significantly decreased its concentration ( Figure 4 b). Using adult rats administered with rosmarinic acid, Liu et al [ 37 ] found a decrease in the expression of ACE. Similarly, in our study, Ang II values decreased in Ro -treated rats.…”

Cardiac fibrosis in the ageing heart: Contributors and mechanisms

“…Recently, Inhibition of the MAPK signalling pathway has been regarded as a potential therapeutic target for ageing‐related fibrosis and other degenerative changes, such as the inhibition of apoptosis singnal regulated kinase 1 (ASK1) (a ROS sensitive kinase belongs to MAKKK family) to alleviate oxidative stress by blocking downstream p38MAPK signalling . Cardiac fibrosis can also be alleviated by other small molecules, including scutellarin, rosmarinic acid and phosphocreatine, through inhibition of MAPK signalling …”

Rosemary supplementation (Rosmarinus oficinallis L.) attenuates cardiac remodeling after myocardial infarction in rats

“…In vivo , rosemary extract supplementation improved the oxidative stress status in the heart of aged rats[19, 20]. Furthermore, rosmarinic acid reduced myocardial damage blood pressure in hypertensive rats fed a high fructose diet[15] and protected the heart against cardiac dysfunction and fibrosis after MI in rats[21]. However, little is known about the effect of rosemary leaves intake in morphology and ventricular function after myocardial injury.…”