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The hydroxamic acid derivative YPX-C-05 alleviates hypertension and vascular dysfunction through the PI3K/Akt/eNOS pathway
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  • Pan-Pan Pang,
  • Hao Sun,
  • Peixia Yu,
  • Weimin Yang,
  • Yong-Tang Zheng,
  • Xun LI,
  • Chang-Bo Zheng
Pan-Pan Pang
Kunming Medical College
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Hao Sun
Shandong University
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Peixia Yu
Shandong University
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Weimin Yang
Kunming Medical University
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Yong-Tang Zheng
Kunming Institute of Zoology, PRC
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Xun LI
Shandong University
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Chang-Bo Zheng
Kunming Medical College

Corresponding Author:[email protected]

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Abstract

Background and Purpose: Hypertension is a chronic medical condition that increases the risk of cardiovascular diseases. Recently, HDAC inhibitors were shown to lower blood pressure through endothelium-dependent mechanisms. However, the antihypertensive potential and precise mechanisms of most HDAC inhibitors remain unexplored. Experimental Approach: We first examined YPX-C-05(a novel hydroxamic acid-based HDAC inhibitor) effects on phenylephrine-induced hypertension in mice. We also determined the vasodilatory effects of YPX-C-05 ex vivo using isolated aortic rings precontracted with phenylephrine. We performed Network pharmacology analysis to predict the putative targets of YPX-C-05. We then validated the involvement of the PI3K/Akt/eNOS pathway using pharmacological inhibitors and Western blotting. Levels of phosphorylated and total Akt and eNOS were measured in Human umbilical vein endothelial cell lysates after YPX-C-05 treatment. In vivo, we examined the chronic antihypertensive effects of YPX-C-05 in N-omega-nitro-L-arginine-induced hypertensive mice. Vascular remodeling was assessed by histological analysis. Key Results: YPX-C-05 could attenuate the hypertensive effects of phenylephrine and reduced blood pressure, increase NO levels, improve endothelium-dependent relaxation and decrease vascular damage in chronic hypertensive mice. Network pharmacology analysis predicted YPX-C-05 might activate endothelial eNOS via PI3K/Akt signaling pathway. Western blotting confirmed that YPX-C-05 increased phosphorylated Akt and eNOS levels and eNOS expression and activity. Conclusion and Implications: This study demonstrates for the first time that the novel hydroxamic acid-based HDAC inhibitor YPX-C-05 exerts significant antihypertensive and vasodilatory effects. Our findings support the developing prospect of YPX-C-05 as a novel antihypertensive drug. Keywords: Hydroxamic acid derivative YPX-C-05; vasodilation; hypertension; vascular function; Akt/eNOS/NO pathway.