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TRPV2 Is Critical for the Maintenance of Cardiac Structure and Function in Mice

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TRPV2 Is Critical for the Maintenance of Cardiac Structure and Function in Mice ARTICLE Received 9 Sep 2013 | Accepted 11 Apr 2014 | Published 29 May 2014 DOI: 10.1038/ncomms4932 OPEN TRPV2 is critical for the maintenance of cardiac structure and function in mice Yuki Katanosaka1, Keiichiro Iwasaki1, Yoshihiro Ujihara1,2, Satomi Takatsu1, Koki Nishitsuji1, Motoi Kanagawa3, Atsushi Sudo3, Tatsushi Toda3, Kimiaki Katanosaka4,5, Satoshi Mohri1,2 & Keiji Naruse1,6 The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca2 þ handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca2 þ -dependent intracellular Ca2 þ increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function. 1 Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata-cho 2-5-1, Okayama city, Okayama 700-8558, Japan. 2 Department of Physiology, Kawasaki Medical School, Matsushima 577, Kurashiki, Okayama 701-0192, Japan. 3 Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. 4 Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan. 5 College of Life and Health Sciences, Chubu University, Matsumoto-cho 1200, Kasugai, Aichi 487-8501, Japan. 6 ICORP-SORST-Cell Mechanosensing Project, Japan Science and Technology Agency, Nagoya, Aichi 466-8550, Japan. Correspondence and requests for materials should be addressed to Y.K. (email: [email protected]). NATURE COMMUNICATIONS | 5:3932 | DOI: 10.1038/ncomms4932 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4932 echanical forces provide essential physiological infor- Results mation for homeostatic regulation and functional Generation of cardiac-specific TRPV2-deficient mice. Madaptation at the levels of cells and organs1.In Initially, mice carrying a TRPV2flox/flox allele were generated by cardiovascular systems, cellular mechanical responses to flanking exon 4 of the TRPV2 gene with two loxP sequences haemodynamic stress are crucial for normal cardiac function, (Supplementary Fig. 1). Excision of this segment resulted in a and affect both the physiological and the pathological growth of frameshift mutation downstream of the deletion sites. Translation the heart2,3. More specifically, an increased cardiac workload from the first ATG gave rise to a short, 92 amino-acid (aa) resulting from exercise, pregnancy or postnatal growth promotes product containing 62 aa of the original TRPV2 protein; however, the physiological growth of the heart, whereas chronic most of the TRPV2 channel structure was lost after Cre-mediated hypertension can cause pathological hypertrophy3. Atrophy of recombination. We crossed mice bearing the TRPV2flox/flox the heart is a complication of protracted bed rest, prolonged allele with a transgenic line (MerCreMer) expressing Cre weightlessness during space travel, and mechanical unloading recombinase under the control of the a-myosin heavy chain with a ventricular assist device3. Despite the obvious influence of promoter in a tamoxifen-inducible cardiomyocyte-specific mechanical load on cardiac structure and function, the molecular manner19 to produce TRPV2flox/flox;MerCreMer þ / À mice. To details of the myocardial mechanotransduction required to account for the deleterious effect of potential nonspecific Cre maintain cardiac structure and function have remained unclear. recombinase-mediated cardiotoxicity20, we used TRPV2flox/ þ ; The heart is a functional syncytium composed of terminally MerCreMer þ / À and TRPV2flox/flox;MerCreMer À / À littermates differentiated myocytes specialized for excitation–contraction as age-matched controls, from which TRPV2flox/flox; (E–C) coupling3. Individual cardiomyocytes are electrically and MerCreMer þ / À mice were indistinguishable in appearance. mechanically coupled at their termini, where highly organized The TRPV2flox/flox;MerCreMer þ / À mice were genotyped by cell–cell junctions known as intercalated discs are located4–6. The PCR using primers for Cre-loxP sites and Cre recombinase structure of intercalated discs is known to be remodelled in (Fig. 1a and Supplementary Fig. 1). In adult TRPV2flox/flox; response to haemodynamic stress7. High wall stress increases the MerCreMer þ / À mice treated with tamoxifen for 3 days (daily myocardial contractile force exerted as a result of cardiac dose of 8 mg kg À 1), we confirmed successful Cre recombination hypertrophy, and the intercalated disc structure has to be by PCR amplification of cardiac genomic DNA, to detect the optimized for physical robustness to adapt to this force3.By deleted allele (Fig. 1b). Consistently, the expression of TRPV2 contrast, mechanical unloading causes cardiac atrophy, messenger RNA was dramatically suppressed in the hearts of accompanied by disorder in the intercalated disc structure7–10. TRPV2-deficient mice on day 3 (Fig. 1c). There was an B95% In addition, human cardiomyopathies have been associated with reduction in TRPV2 protein in membrane extracts of cardiac mutations in genes encoding components of intercalated muscle from these mice after 4 days of tamoxifen treatment discs, involved in mechanical coupling, and studies in mice and (Fig. 1d). Consistently, the TRPV2 protein was also not detectable humans have suggested a connection between faulty myocardial by immunofluorescent staining at intercalated discs in the hearts mechanical coupling mechanisms and heart disease11–15. of these mice, although TRPV2 was highly localized to Flexibility in cardiac adaptation to haemodynamic stress intercalated discs in control mice (Fig. 1e). Hereafter, in this probably requires the maintenance of intercalated disc structure study, we treated TRPV2flox/flox;MerCreMer þ / À , TRPV2flox/ þ ; and function by continuous monitoring of the mechanical stress MerCreMer þ / À and TRPV2flox/flox;MerCreMer À / À mice with at intercalated discs. Therefore, we hypothesized that cardiac 8mgkgÀ 1 per day tamoxifen or vehicle for 4 consecutive days, mechanoreceptors at intercalated discs detect mechanical stress in then carried out analyses at different time points. the heart, maintaining myocardial structure and function in response to haemodynamic stress through the mechanical feedback system in cardiomyocytes. The chamber dilation in TRPV2-deficient hearts. Paraffin Members of the transient receptor potential (TRP) cation sections from TRPV2-deficient hearts were treated with Masson’s channel family are potential candidates for the mechanoreceptors trichrome stain and analysed histologically. After 4 days of responding to tension, flow or changes in cell volume16. tamoxifen treatment, hearts from TRPV2flox/flox;MerCreMer þ / À Previously, we reported that recombinant TRP, vanilloid mice were morphologically normal with no incremental changes family type 2 (TRPV2) can be activated by hypotonicity- and in the heart weight/body weight ratio or the cross-sectional area stretch-induced mechanical stimulation in ectopic expression of the cardiomyocytes (Fig. 2a–d). However, 9 days after the onset systems17,18. Interestingly, TRPV2 is highly localized to of tamoxifen treatment, the chambers of the hearts from these mammalian cardiac intercalated discs, and its increased mice were enlarged, as seen in the final phase of dilated cardio- expression at the sarcolemma is observed in dystrophic human myopathy (Fig. 2a). This dilation differed from ventricular patients and animal models deficient in dystrophin or hypertrophy as the ventricle wall was not thickened. As evidence d-sarcoglycan17. To elucidate the physiological role of cardiac of this, within 10 days of the onset of tamoxifen administration, TRPV2, we generated temporally controlled cardiac-specific the heart weight/body weight ratio and cardiomyocyte cross- TRPV2-deficient mice. Cardiac-specific TRPV2 elimination led sectional area in TRPV2-deficient hearts were comparable with to a severe decline in the heart’s pump function with the those of control mice (Fig. 2b,c). In addition, the cardiomyocytes disorganization of the intercalated disc structure, conduction of TRPV2-deficient mice showed no cellular degeneration or defects and accelerated mortality. TRPV2-deficient neonatal intermuscular fibrosis (Fig. 2d). Whereas the cell–cell interfaces cardiomyocytes formed no intercalated discs and showed no forming intercalated discs ran perpendicular to the muscle fibres extracellular Ca2 þ -dependent
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