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. 2024 Feb 28;25(5):2806.
doi: 10.3390/ijms25052806.

Piper sarmentosum Roxb. Inhibits Angiotensin-Converting Enzyme Activity in Phorbol 12-Myristate-13-Acetate-Induced Endothelial Cells

Azizah Ugusman  1 , Siti Marjiana Ismail  1   2 , Nur Syahidah Nor Hisam  1   3 , Chua Kien Hui  1 , Mohammed S M Saleh  4 , Abdul Kadir Abdul Karim  5 , Nur Syakirah Othman  1 , Adila A Hamid  1 , Amilia Aminuddin  1
Affiliations

Piper sarmentosum Roxb. Inhibits Angiotensin-Converting Enzyme Activity in Phorbol 12-Myristate-13-Acetate-Induced Endothelial Cells

Azizah Ugusman et al. Int J Mol Sci. .

Abstract

Angiotensin-converting enzyme (ACE) plays a crucial role in the pathogenesis of hypertension. Piper sarmentosum Roxb., an herb known for its antihypertensive effect, lacks a comprehensive understanding of the mechanism underlying its antihypertensive action. This study aimed to elucidate the antihypertensive mechanism of aqueous extract of P. sarmentosum leaves (AEPS) via its modulation of the ACE pathway in phorbol 12-myristate-13-acetate (PMA)-induced human umbilical vein endothelial cells (HUVECs). HUVECs were divided into five groups: control, treatment with 200 µg/mL AEPS, induction 200 nM PMA, concomitant treatment with 200 nM PMA and 200 µg/mL AEPS, and treatment with 200 nM PMA and 0.06 μM captopril. Subsequently, ACE mRNA expression, protein level and activity, angiotensin II (Ang II) levels, and angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) mRNA expression in HUVECs were determined. AEPS successfully inhibited ACE mRNA expression, protein and activity, and angiotensin II levels in PMA-induced HUVECs. Additionally, AT1R expression was downregulated, whereas AT2R expression was upregulated. In conclusion, AEPS reduces the levels of ACE mRNA, protein and activity, Ang II, and AT1R expression in PMA-induced HUVECs. Thus, AEPS has the potential to be developed as an ACE inhibitor in the future.

Keywords: Piper sarmentosum; angiotensin converting enzyme; human umbilical vein endothelial cells; hypertension; phorbol 12-myristate-13-acetate.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The LC-MS analysis of aqueous extract of P. sarmentosum leaves. Peaks are identified with numbers according to the elution order (refer to Table 1).
Figure 2
Figure 2
Determination of the optimum concentrations of PMA, AEPS, and captopril for HUVEC treatments based on ACE activity. (A) ACE activity in HUVECs induced with 100–300 nM PMA, (B) ACE activity in PMA-induced HUVECs upon treatment with different concentrations of AEPS (100–300 µg/mL), and (C) ACE activity in PMA-induced HUVECs upon treatment with different concentrations of captopril (0.02–0.06 µM). Values are expressed as mean ± SEM, n = 6. * p < 0.05, ** p < 0.01 compared with the untreated control, # p < 0.05, ## p < 0.01, ### p < 0.001 compared with the PMA group. ACE, angiotensin-converting enzyme; AEPS, aqueous extract of Piper sarmentosum leaves; PMA, phorbol 12-myristate-13-acetate.
Figure 3
Figure 3
Effects of AEPS treatment on (A) ACE mRNA expression and (B) ACE protein levels in HUVECs induced with PMA. Values are expressed as mean ± SEM, n = 6. *** p < 0.001 compared with control, ## p < 0.01, ### p < 0.001 compared with PMA group. ACE, angiotensin-converting enzyme; AEPS, aqueous extract of Piper sarmentosum leaves; PMA, phorbol 12-myristate-13-acetate.
Figure 4
Figure 4
Effects of AEPS treatment on ACE activity in PMA-induced HUVECs. Values are expressed as mean ± SEM, n = 6. ** p < 0.01 compared with control. ## p < 0.01 compared with PMA group. ACE, angiotensin-converting enzyme; AEPS, aqueous extract of Piper sarmentosum leaves; PMA, phorbol 12-myristate-13-acetate.
Figure 5
Figure 5
Effects of AEPS treatment on angiotensin II protein levels in PMA-induced HUVEC. Values are expressed as mean ± SEM, n = 6. *** p < 0.001 compared with control. # p < 0.05, ### p < 0.001 compared with PMA group. ACE, angiotensin-converting enzyme; AEPS, aqueous extract of Piper sarmentosum leaves; PMA, phorbol 12-myristate-13-acetate.
Figure 6
Figure 6
Effect of AEPS on (A) AT1R and (B) AT2R mRNA expressions in PMA-induced HUVEC. Values are expressed as mean ± SEM, n = 6. * p < 0.05, ** p < 0.01 compared with control. ## p < 0.01, ### p < 0.001 compared with PMA group. ACE, angiotensin-converting enzyme; AEPS, aqueous extract of Piper sarmentosum leaves; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; PMA, phorbol 12-myristate-13-acetate.
Figure 7
Figure 7
Effect of AEPS on ex vivo aortic contraction to PMA. Values are expressed as mean ± SEM, n = 6. *** p < 0.001 compared with control. AEPS, aqueous extract of Piper sarmentosum leaves; PMA, phorbol 12-myristate-13-acetate.
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