The Complex Regulation of Tanshinone IIA in Rats with Hypertension-Induced Left Ventricular Hypertrophy

Abstract

Tanshinone IIA has definite protective effects on various cardiovascular diseases. However, in hypertension-induced left ventricular hypertrophy (H-LVH), the signaling pathways of tanshinone IIA in inhibition of remodeling and cardiac dysfunction remain unclear. Two-kidney, one-clip induced hypertensive rats (n = 32) were randomized to receive tanshinone IIA (5, 10, 15 mg/kg per day) or 5% glucose injection (GS). Sham-operated rats (n = 8) received 5%GS as control. Cardiac function and dimensions were assessed by using an echocardiography system. Histological determination of the fibrosis and apoptosis was performed using hematoxylin eosin, Masson’s trichrome and TUNEL staining. Matrix metalloproteinase 2 (MMP2) and tissue inhibitor of matrix metalloproteinases type 2 (TIMP2) protein expressions in rat myocardial tissues were detected by immunohistochemistry. Rat cardiomyocytes were isolated by a Langendorff perfusion method. After 48 h culture, the supernatant and cardiomyocytes were collected to determine the potential related proteins impact on cardiac fibrosis and apoptosis. Compared with the sham rats, the heart tissues of H-LVH (5%GS) group suffered severely from the oxidative damage, apoptosis of cardiomyocytes and extracellular matrix (ECM) deposition. In the H-LVH group, tanshinone IIA treated decreased malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity. Tanshinone IIA inhibited cardiomyocytes apoptosis as confirmed by the reduction of TUNEL positive cardiomyocytes and the down-regulation of Caspase-3 activity and Bax/Bcl-2 ratio. Meanwhile, plasma apelin level increased with down-regulation of APJ receptor. Tanshinone IIA suppressed cardiac fibrosis through regulating the paracrine factors released by cardiomyocytes and the TGF-β/Smads signaling pathway activity. In conclusion, our in vivo study showed that tanshinone IIA could improve heart function by enhancing myocardial contractility, inhibiting ECM deposition, and limiting apoptosis of cardiomyocytes and oxidative damage.

Retracted: Tanshinone IIA prevents left ventricular remodelling via the TLR4/MyD88/NF‐κB signalling pathway in rats with myocardial infarction

“…A previous study indicated that the ideal therapy for MI‐induced cardiac injury was to inhibit the reactive fibrosis (and other remodelling processes) as well as the regeneration of the infarct area in non‐infarcted areas 32. Tanshinone IIA suppresses cardiac fibrosis by regulating the paracrine factors released by cardiomyocytes that go on to activate the TGF‐b/Smads signalling pathway 9. Tan IIA could also mitigate BLM‐induced pulmonary fibrosis and suppress the TGF‐β‐dependent mesenchymal transition (EMT) in lung alveolar epithelial cells 33…”

“…Tanshinone IIA is used for treating cardiovascular diseases including cardiac hypertrophy, heart failure and myocardial ischaemia‐reperfusion injury, which could improve heart function by reducing the degree of fibrosis and inhibiting the apoptosis of cardiomyocytes 9. It has been reported that tanshinone IIA is a popular and safe herb medicine, which showed a protective effect on the endothelial cells 10.…”

The role of TIMPs in regulation of extracellular matrix proteolysis

“…For instance, correlative data supports a role for TIMP2 in protecting the ECM from proteolysis in fracture healing [30], keloids [31], liver [32,33], kidneys [34,35], Dupuytren's contracture [36,37], and in heart tissues [38][39][40][41][42]. As a specific example, patients suffering from Dupuytren's contracture, a disease caused by excessive ECM deposition leading to fixed flexion of joints in the hand, have a disruption in the balance between TIMP2 and MMP2 in favor of TIMP2, which suggests that increased TIMP2 is associated with pathophysiological ECM accumulation [36,37].…”

Tanshinone IIA effects on ovarian cancer cell line

“…Tanshinone IIA is the active component isolated from Danshen (also known as Salvia miltiorrhiza ), which possess high medicinal values in the traditional Chinese medicine (TCM) against diverse cardiovascular and cerebrovascular diseases including angina pectoris, myocardial infarction, hyperlipidaemia, hypertension and acute ischaemic stroke . Array of active ingredients has been identified in the Danshen extract that consists of antioxidant salvianolic acid, dihydrotanshinone, Tanshinone I and Tanshinone II, wherein the Tanshinone IIA is the most abundant.…”