Biochemical and Biophysical Research Communications
Increased transient receptor potential vanilloid type 1 (TRPV1) channel expression in hypertrophic heart
Research highlights
► Transient receptor potential vanilloid type 1 (TRPV1) channels may cause heart hypertrophy. ► TRPV1 transcripts were increased in transgenic mice overexpressing the catalytic subunit alpha of protein phosphatase 2A alpha (PP2Ac alpha). ► Discoidin domain receptor family, member 2 was significantly higher in PP2Ac compared to wild-type mice and TRPV1 knockout mice. ► The expression of miR21 was significantly higher in PP2Ac alpha compared with TRPV1 knockout mice. ► The study suggests an important role of TRPV1 in the pathogenesis of genetically associated heart hypertrophy.
Introduction
The role of transient receptor potential (TRP) cation channels in cardiovascular function and disease is increasingly recognized. TRP-mediated calcium influx is thought to be essential for heart hypertrophy and specific TRP subtypes have been found to mediate receptor-stimulated and pressure-overload induced heart hypertrophy [1]. Heart hypertrophy may be mediated by increased formation of cardiac para- and/or autocrine factors including endothelin-1, norepinephrine or angiotensin II, the receptors of which are coupled to G-proteins [2]. Downstream signaling pathways involve activation of phospholipase C causing increased formation of diacylglycerol, which is known to activate transient receptor potential vanilloid type 1 (TRPV1) cation channels. TRPV1 channels have been described in sensory nerve fibers in the heart [3]. The activation state of the TRPV1 receptors has been shown to be associated with cardiac functions, i.e. heart rate and inotropy [4].
We investigated the role of TRPV 1 in respect to heart hypertrophy in two specific (different) genetically modified mice models. Since it has been shown by our group that overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function, this model was chosen for research in the present study [5]. The basis for the investigated genetically modified mouse model is the fact that protein phosphatase 2A, which is a multifunctional protein phosphatase with critical roles in excitable cell signals, and which has been suggested to regulate key ion channels and transporters [6], dephosphorylates phospholamban, an intrinsic membrane protein of the cardiac sarcoplasmic reticulum. Dephosphorylation of phospholamban in turn reduces the activity of the cardiac sarcoplasmic reticulum calcium ATPase, causing reduced filling of intracellular stores. Hence, dephosphorylation of phospholamban leads to reduced heart inotropy. We tested the hypothesis that in this novel genetic model of impaired cardiac function induced by cardiac specific overexpression of the catalytic subunit of protein phosphatase 2A, TRPV1 expression correlates with heart hypertrophy. Wild-type mice as well as TRPV1 knockout mice served as controls. Transcripts of TRPV1 together with a marker of myocardial fibrosis (matrix metalloproteinase 9; MMP9), a marker of heart failure (atrial natriuretic peptide; ANP), the heart failure-associated transcription factor GATA 4, and regulatory microRNA (miR-21) associated with heart failure [7] were analyzed using quantitative real-time PCR.
Section snippets
Animals
Transgenic mice showing overexpression of the catalytic subunit alpha of protein phosphatase 2A (PP2Ac alpha) were used as described by us previously [5]. The NotI–SalI restriction enzyme fragment encoding mouse PP2Ac alpha along with its 5′- and 3′-untranslated regions was excised from the reverse transcriptase–PCR product and ligated into the same sites of a mouse cardiac alpha-myosin heavy chain promoter expression cassette containing the SV40 transcriptional terminator. The transgene
Heart hypertrophy in PP2Ac alpha transgenic mice
Ventricle-to-body-weight-ratio was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1 knockout mice (8.6 ± 1.3 mg/g; 5.4 ± 0.3 mg/g; and 5.4 ± 0.4 mg/g; respectively; p < 0.05 by Kruskal–Wallis test), indicating heart hypertrophy in transgenic mice (Fig. 1A). The expression of PP2Ac alpha transcripts were significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1 knockout mice (3.63 ± 1.26 arbitrary units; 0.18 ± 0.04 arbitrary units; 0.01 ±
Discussion
The present study showed an increased expression of TRPV1 cation channels in hypertrophic hearts. Transgenic mice had significantly elevated expression of both PP2Ac alpha transcripts and TRPV1 transcripts compared to wild-type mice and TRPV1 knockout mice, supporting the association between PP2Ac alpha and TRPV1 expression. We showed a significant correlation between TRPV1 expression and ventricle-to-body-weight-ratio in wild-type mice and transgenic mice showing an overexpression of the
Conflict of interest
None.
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MiR-21 involve in ERK-mediated upregulation of MMP9 in the rat hippocampus following cerebral ischemia
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