Phosphodiesterase 4D promotes angiotensin II-induced hypertension in mice via smooth muscle cell contraction

Tianfei Fan,Weipeng Ge,Xiaohang Feng,Yangfeng Hou,Xiaomin Song,Jing Wang,Ran Gao,Wenjun Guo,Tianhui Fan

doi:10.1038/s42003-022-03029-0

Abstract

Hypertension is a common chronic disease, which leads to cardio-cerebrovascular diseases, and its prevalence is increasing. The cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway participates in multiple cardiovascular diseases. Phosphodiesterase (PDE) 4 has been shown to regulate PKA activity via cAMP specific hydrolysis. However, whether PDE4-cAMP-PKA pathway influences hypertension remains unknown. Herein, we reveal that PDE4D (one of PDE4 isoforms) expression is upregulated in the aortas of experimental hypertension induced by angiotensin II (Ang II). Furthermore, knockout of Pde4d in mouse smooth muscle cells (SMCs) attenuates Ang II-induced hypertension, arterial wall media thickening, vascular fibrosis and vasocontraction. Additionally, we find that PDE4D deficiency activates PKA-AMP-activated protein kinase (AMPK) signaling pathway to inhibit myosin phosphatase targeting subunit 1 (MYPT1)-myosin light chain (MLC) phosphorylation, relieving Ang II-induced SMC contraction in vitro and in vivo. Our results also indicate that rolipram, a PDE4 inhibitor, may be a potential drug for hypertension therapy.

Highlights

Hypertension is a common chronic disease, which leads to cardio-cerebrovascular diseases, and its prevalence is increasing
Using phenylephrine (PE) and angiotensin II (Ang II) to induce mesenteric arterioles contraction, we found that the vasocontraction was markedly suppressed in Pde4dSMC−/− mice compared with Pde4dflox/flox mice (Pde4dflox/flox + Ang II group vs. Pde4dSMC−/− + Ang II group; 10−5 M PE: 175.53% ± 5.52% vs. 130.42% ± 10.79%, 25.7% reduced by Pde4dSMC−/− + Ang II group; 10−7 M Ang II: 214.38% ± 25.3% vs. 132.08% ± 12.6%, 38.39% reduced by Pde4dSMC−/− + Ang II group; Fig. 3a, b)
Via endothelial cell (EC)- and smooth muscle cells (SMCs)-specific Pde4d knockout hypertensive mice, these models revealed a causal association between SMC Pde4d and vasocontraction in hypertension

Summary

Introduction

Hypertension is a common chronic disease, which leads to cardio-cerebrovascular diseases, and its prevalence is increasing. The cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway participates in multiple cardiovascular diseases. Whether PDE4-cAMP-PKA pathway influences hypertension remains unknown. Knockout of Pde4d in mouse smooth muscle cells (SMCs) attenuates Ang II-induced hypertension, arterial wall media thickening, vascular fibrosis and vasocontraction. We find that PDE4D deficiency activates PKA-AMP-activated protein kinase (AMPK) signaling pathway to inhibit myosin phosphatase targeting subunit 1 (MYPT1)-myosin light chain (MLC) phosphorylation, relieving Ang II-induced SMC contraction in vitro and in vivo. PDE4 participates in a variety pathophysiological processes[11], promoting SMCs’ phenotypic switch and neointima formation in atherosclerosis[12], as well as aggravating pulmonary arterial hypertension through the regulation of vascular tone and inflammatory factors[13]. AMPK inhibitor aggravated SMCs contraction and hypertension by activating MYPT1-MLC signaling pathway[20]. It is hypothesized that PDE4 may affect SMCs contraction by PKA-AMPK-MYPT1-MLC pathway and affect hypertension

Methods

Results

Conclusion