Journal
HYPERTENSION
Volume 67, Issue 4, Pages 763-773Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.115.07021
Keywords
blood pressure; downregulation; hypertension; magnesium; signal transduction
Categories
Funding
- Canadian Institute of Health Research [FRN57786]
- National Institutes of Health [PO1 GM078195]
- Canada Research Chair/Canadian Foundation for Innovation award
- British Heart Foundation Chair [CH/12/4/29762]
- British Heart Foundation [RG/13/7/30099] Funding Source: researchfish
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Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg2+)/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7kinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7kinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg2+ was lower in TRPM7kinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7kinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7kinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7kinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II-treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7kinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage.
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