Abstract
Left ventricular hypertrophy (LVH) is an important characteristic of hypertensive heart disease. Renin-angiotensin system (RAS) blockers have been shown to be effective drugs for the reversal of LVH. Clinical and experimental studies have shown that Zi Shen Huo Luo Formula (ZSHLF) can improve the efficacy of perindopril in the treatment of hypertensive LVH, but its mechanism is unclear. This study aimed to investigate the possible mechanism to improve the efficacy of perindopril. First, we identified 23 compounds in ZSHLF by ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis, among which ferulic acid, caffeic acid, vanillic acid, berberine, rutin, quercetin, kaempferol, stachydrine, and tiliroside have been reported to reduce blood pressure and exhibit cardioprotective effects. Second, we treated spontaneously hypertensive rats (SHRs) with perindopril and ZSHLF for 12 continuous weeks and found that chronic use of perindopril could increase the aldosterone (ALD) levels and cause aldosterone breakthrough (ABT). ZSHLF combined with perindopril reduced the ALD levels, interfered with ABT, decreased blood pressure, improved left ventricular diastolic dysfunction, and decreased the collagen volume fraction; these effects were superior to those of perindopril alone. In vitro experiments, ALD-induced cardiomyocytes (H9c2 cells) and cardiac fibroblasts were treated with ZSHLF-containing serum, which suppressed ALD-induced cardiomyocyte hypertrophy and cardiac fibroblast proliferation, increased mineralocorticoid receptor (MR) and Cav-1 colocalization and decreased phosphorylated epidermal growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase (pERK) protein expression the cells. In conclusion, ZSHLF can interfere with ABT and affect the pathological role of ALD by affecting MR and Cav-1 interactions and EGFR/ERK signaling pathway. These effects represent a possible mechanism by which ZSHLF improves the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) in hypertensive LVH treatment. However, the major bioactive components or metabolites responsible for the effects and the implications of these findings in patients need further verification.
Highlights
Left ventricular hypertrophy (LVH) is an important characteristic of hypertensive heart disease that mainly involves cardiomyocyte hypertrophy and fibrosis due to cardiac fibroblast proliferation
Our results suggest that ZSHLF can improve the efficacy of perindopril in the treatment of hypertensive LVH and that the effect may be related to interference with aldosterone breakthrough (ABT) and inhibition of ALD-induced pathological remodeling
The serum ALD levels in the ZSHLF group remained low and were lower than those in the SHR and PEP groups. These findings suggested that the ABT phenomenon occurred during the course of perindopril treatment and that ZSHLF could effectively limit the occurrence of ABT
Summary
Left ventricular hypertrophy (LVH) is an important characteristic of hypertensive heart disease that mainly involves cardiomyocyte hypertrophy and fibrosis due to cardiac fibroblast proliferation. RAS blockers lower plasma aldosterone (ALD) levels at the beginning of treatment, but the ALD levels may return to or exceed the pretreatment values as the treatment time increases. This phenomenon is known as aldosterone breakthrough (ABT), and it may limit the beneficial effects of RAS blockers (Christ et al, 2004; Ubaid-Girioli et al, 2007). Strongly interfering with ABT and controlling the cardiac hypertrophy induced by elevated ALD are important strategies for improving the efficacy of RAS blockers and reducing the risk of cardiovascular risk events
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