Published online before print February 7, 2008, doi: 10.1161/CIRCRESAHA.107.160077
© 2008 American Heart Association, Inc.
Integrative Physiology |
Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension
From the Institut National de la Santé et de la Recherche Médicale (E.L., J.P., A.B., L.M., J.-P.H., L.B.), U702, Paris; Université Pierre et Marie Curie-Paris6 (E.L., J.P., A.B., L.M., J.-P.H., L.B.), UMRS702, Paris; Assistance Publique-Hôpitaux de Paris (E.L., A.B., J.-P.H., L.B.), Tenon Hospital, Department of Physiology, Paris; and Centre National de la Recherche Scientifique (A.d.C.K.), UMR8147, Paris, France.
Correspondence to Laurent Baud, MD, PhD, INSERM U702, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. E-mail laurent.baud{at}tnn ap-hop-paris.fr
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Abstract |
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In hypertension, angiotensin (Ang) II is a critical mediator of cardiovascular remodeling, whose prominent features include myocardial and vascular media hypertrophy, perivascular inflammation, and fibrosis. The signaling pathways responsible for these alterations are not completely understood. Here, we investigated the importance of calpains, calcium-dependent cysteine proteases. We generated transgenic mice constitutively expressing high levels of calpastatin, a calpain-specific inhibitor. Chronic infusion of Ang II led to similar increases in systolic blood pressure in wild-type and transgenic mice. In contrast, compared with wild-type mice, transgenic mice displayed a marked blunting of Ang II–induced hypertrophy of left ventricle. Ang II–dependent vascular remodeling, ie, media hypertrophy and perivascular inflammation and fibrosis, was also limited in both large arteries (aorta) and small kidney arteries from transgenic mice as compared with wild type. In vitro experiments using vascular smooth muscle cells showed that calpastatin transgene expression blunted calpain activation by Ang II through epidermal growth factor receptor transactivation. In vivo and in vitro models of inflammation showed that impaired recruitment of mononuclear cells in transgenic mice was attributable to a decrease in both the release of and the chemotactic response to monocyte chemoattractant protein-1. Finally, results from collagen synthesis assay and zymography suggested that limited fibrogenesis was attributable to a decrease in collagen deposition rather than an increase in collagen degradation. These results indicate a critical role for calpains as downstream mediators in Ang II–induced cardiovascular remodeling and, thus, highlight an attractive therapeutic target.
Key Words: angiotensin • calpain • remodeling • nuclear factor-
-B
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Introduction |
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Cardiovascular damages in hypertension represent a growing public health problem.1 Among them, vascular remodeling is an adaptive response to increased arterial blood pressure. This process results from coordinated proliferation and differentiation of vascular smooth muscle cells (VSMCs), together with inflammation and extracellular matrix deposition. One of the most important factors involved in arterial remodeling is angiotensin (Ang) II, a key effector of the renin–angiotensin–aldosterone system.2,3 In addition to its role in arterial blood pressure regulation (ie, via vasoconstriction and retention of sodium and water), Ang II induces VSMC hyperplasia and hypertrophy through the transactivation of epidermal growth factor (EGF), platelet-derived growth factor, and insulin-like growth factor I receptors.4 It is also critically involved in the initial stage of inflammation, increasing vascular permeability and leukocyte recruitment through the expression of vascular endothelial growth factor (VEGF) and adhesion molecules or chemokines, respectively.2,3 In addition, Ang II participates to fibrosis process through the production of transforming growth factor-β, platelet-derived growth factor, and endothelin-1, as well as by attenuating interstitial matrix metalloproteinase (MMP) activity. Most of these effects are mediated by Ang II type 1 (AT1) rather than type 2 (AT2) receptors. Ang II/AT1 receptor interaction generates an immediate calcium-dependent response and a late nuclear factor (NF)-
B activation through the activation of different pathways including protein kinase C, mitogen-activated protein kinase, receptor tyrosine kinases (eg, EGF receptor [EGFR]), and nonreceptor tyrosine kinases (eg, Src).4
Calpains are calcium-activated neutral cysteine proteases involved in the activation of NF-B.5,6 Two major isoforms, calpain µ (or 1) and calpain m (or 2), are ubiquitously expressed, whereas the other isoforms are tissue-specific forms. All calpain isoforms are present in the cytosol as inactive proenzymes. Binding of calcium to µ- or m-calpain induces the release of constraints imposed by domain interactions and results in a 2-stage activation process, with the first involving the release of an 
30-kDa regulatory subunit and second involving the rearrangement of the active site cleft in an 80-kDa catalytic subunit.7 In the absence of cytosolic calcium flux, calpain can be activated by EGFR engagement, via direct phosphorylation by mitogen-activated protein kinase.8
Calpain activity, which is tightly controlled by calpastatin, a specific endogenous inhibitor,5 plays an important role in acute inflammatory process.9–11 Indeed, these enzymes are involved in the activation of NF-B12 and thereby in the NF-B–dependent expression of proinflammatory cytokines and adhesion molecules. Thus, because of the parallels between Ang II– and calpain-dependent NF-B activation, we wondered whether calpains could contribute to mechanisms underlying Ang II–dependent cardiovascular remodeling in vivo.
To answer this question, we took advantage of the availability of mice expressing high levels of calpastatin recently generated in our laboratory.13 Using these transgenic mice, we ascertained the functions of calpains in Ang II–mediated vascular remodeling, with special focus on the role of Ang II on hypertrophy, inflammation and fibrosis processes.
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Materials and Methods |
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An expanded Materials and Methods is in the online data supplement, available at http://circres.ahajournals.org.
Calpastatin transgenic (CalpTG) mice were created and characterized in the laboratory.13 Ang II was infused subcutaneously (1.8 µg/kg per min) using osmotic minipumps for 4 weeks. Systolic blood pressure (SBP) was measured twice per week in conscious animals by tail plethysmography via a tail cuff apparatus. Specimens of kidney, heart, and aorta were cut for histochemistry and immunohistochemistry studies. Calpain, myeloperoxidase, and gelatinase activities were determined in tissue samples as described previously.11,13 Nuclear proteins were extracted from these tissue samples, and the amounts of activated NF-B p65 subunit and nuclear factor of activated T cells (NFAT)c3 were measured with a commercial kit and Western blot assay, respectively. VSMCs were isolated from digested aorta, as previously described.14 These cells were pulsed with [3H]leucine and [3H]proline to determine protein and collagen synthesis, respectively. Peritoneal mononuclear cells were isolated as described previously15 to analyze their capacity to generate chemokines and to migrate in response to chemokine gradient.
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Results |
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Characterization of Calpastatin Transgenic Mice
To localize the transgene product, we compared the expression of calpastatin in wild-type (WT) and CalpTG mice, by using a monoclonal antibody that recognizes both rabbit and mouse calpastatin. Because large elastic arteries and small resistance arteries play different roles in the mechanisms and complications of hypertension,16 we analyzed the wall of aorta and kidney interlobular arteries, respectively. We chose kidney vasculature because Ang II causes hypertension and its cardiovascular complications primarily through effects on AT1 receptors in the kidney.17 Calpastatin staining increased markedly in heart, aorta, and kidney of CalpTG mice, especially in the adventitia of aorta and the media of interlobular arteries (Figure 1a). Western blot analyses of kidney confirmed this difference in the calpastatin expression (Figure 1b). Such a calpastatin excess had no effect on its own on calpain activity, as judged by measuring the accumulation of 145/150-kDa spectrin BDP in kidney (Figure 1b) and heart (Figure I in the online data supplement). In addition, calpastatin excess did not lead to alterations in calpain 1 (data not shown) and calpain 2 expression (Figure 1b).
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To assess the role of calpains in Ang II–dependent hypertension and cardiovascular remodeling, osmotic minipumps were implanted subcutaneously into both WT and CalpTG mice. They infused Ang II (1800 ng/kg per min) or vehicle (0.9% saline) continuously for 4 weeks. In WT mice, Ang II perfusion resulted in a significant increase in calpain activity, together with a significant decrease in calpastatin expression, suggesting a degradation of calpastatin by calpains within the kidney (Figure 1b). In contrast, in CalpTG mice, Ang II perfusion did not increase calpain activity.
Thus, calpastatin transgene expression results in an impairment in the Ang II–dependent calpain activation.
Ang II–Dependent Hypertension in WT and CalpTG Mice
SBP values were identical in WT, heterozygous CalpTG, and homozygous CalpTG control mice (Figure 2). On initiation of Ang II delivery, SBP values rose progressively to almost 170 mm Hg and remained elevated throughout the study period (4 weeks). The degree of SBP increase was similar in WT and CalpTG mice. In spite of this increase in SBP, glomerular filtration rate did not decrease significantly, as determined by measuring either plasma creatinine (15.5±2.4, 14.5±2.0, 27.0±2.4, and 21.9±2.7 µmol/L in WT, TG, WT Ang II, and TG Ang II, respectively; N=4 to 9) or plasma urea (12.0±0.9, 10.9±0.4, 12.4±1.1, and 10.9±1.1 mmol/L in WT, TG, WT Ang II, and TG Ang II, respectively; N=4 to 9). Thus, Ang II causes hypertension through calpain-independent mechanisms.
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Ang II–Dependent Cardiovascular Hypertrophy in WT and CalpTG Mice
Ang II, by signaling through AT1 receptor, induces vascular wall thickening that involves hypertrophy, hyperplasia, and migration of VSMCs. To assess the role of calpains in this process, media cross-sectional area of aorta and kidney interlobular arteries were determined (Figure 3a and 3b). Ang II infusion promoted a medial wall thickening that was, in large part, prevented in CalpTG mice. To determine whether calpastatin transgene expression directly affects Ang II–induced hypertrophic response in VSMCs, we measured [3H]leucine incorporation in mouse aortic VSMCs in primary culture. The presence of the transgene completely suppressed their response to Ang II (Figure 3c). To gain mechanistic insight, we examined the direct effect of Ang II on VSMC calpain activity. Aortic VSMCs derived from WT type mice showed a time-dependent increase in calpain activity on exposure to Ang II, whereas those from CalpTG mice showed a limited response (Figure 3d). Binding of Ang II to AT1 receptor is thought to cause a transactivation of the EGFR.4 Because EGFR engagement is associated with calpain activation,18 we analyzed the effects of both an AT1 receptor antagonist (losartan) and an EGFR tyrosine kinase inhibitor (AG1478) on VSMC response to Ang II. The 2 drugs prevented completely the Ang II–dependent increase in calpain activity (Figure 3e). Finally, an identical increase in Ang II–induced EGFR phosphorylation was observed in VSMCs from WT and CalpTG mice (Figure 3f), indicating that calpastatin transgene expression affected calpain activity downstream of EGFR transactivation. Collectively, our data suggest that Ang II perfusion results in a vascular wall thickening that would require calpain activation through both Ang II binding to AT1 receptor and EGFR transactivation.
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) and CalpTG mice (
). Ang II-induced [3H]leucine incorporation was suppressed in VSMCs derived from the aorta of CalpTG mice as compared with WT mice. Results are means±SEM of 3 separate experiments (P<0.0005; ANOVA). A photomicrograph of cultured VSMCs fixed and stained with anti-SMA antibody (green) and 4',6-diamidino-2-phenylindole (DAPI) (blue) is shown. d, In vitro assessment of the effects of Ang II on calpain activity in aortic VSMCs derived from WT (In addition to vascular hypertrophy, chronic hypertension causes left ventricular hypertrophy.17 Thus, we compared the heart weight/body weight ratios in WT and CalpTG mice. After 4 weeks of Ang II infusion, WT mice developed a robust cardiac hypertrophy, the extent of which was reduced in CalpTG mice in proportion to transgene expression (Figure 4a). To further document cardiac hypertrophy, we performed morphometric analyses by counting the number of cardiomyocyte nuclei per surface of heart section and by measuring cardiomyocyte cross-sectional areas.19,20 The 2 quantifications confirmed that Ang II infusion induced a stronger hypertrophy in WT mice than in CalpTG mice (Figure 4b and 4c).
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Ang II–Dependent Perivascular Inflammation in WT and CalpTG Mice
Ang II induces vascular inflammatory response through both blood pressure–dependent and –independent mechanisms.21 Infiltration of monocytes/macrophages, lymphocytes, and, to a lesser extent, neutrophils was indeed markedly increased in the adventitia of aorta (data not shown) and kidney interlobular arteries (Figure 5a) of mice receiving Ang II. Inflammatory cells were activated, as evidenced by the appearance of a myeloperoxidase activity in the kidney cortex (Figure 5b). All of these changes were dramatically attenuated in CalpTG mice (Figure 5a and 5b). Because Ang II directly increases leukocyte infiltration by upregulating the expression of chemokines and adhesion molecules in vascular cells and by activating blood inflammatory cells,21 we next examined in vitro the capacity of vascular cells and blood mononuclear cells to generate chemokines and to migrate in response to chemokine gradient, respectively. Aortic VSMCs derived from WT type mice showed a dose-dependent increase in monocyte chemoattractant protein (MCP)-1 expression on exposure to Ang II, whereas those from CalpTG mice did not (Figure 5c). In addition, mononuclear cells from the peritoneum of WT mice migrated in response to MCP-1 gradient, whereas those from CalpTG mice did not (Figure 5d).
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To confirm the mechanisms by which calpain inactivation regulates inflammatory cell recruitment, we used the in vivo inflammation model induced by the intraperitoneal injection of thioglycollate. Inflammatory challenge into the abdominal cavity of WT mice led to a time-dependent recruitment of neutrophils, monocytes, and lymphocytes that peaked at 4, 16, and 48 hours, respectively (Figure 5e). Again, CalpTG mice had an impaired (neutrophils) and delayed (monocytes and lymphocytes) ability to recruit inflammatory cells. However, WT and CalpTG mice showed no difference in peritoneal lymphocyte subpopulations (supplemental Table I). Defective recruitment of leukocytes into thioglycollate-induced peritonitis was not attributable to a failure in lymphohematopoiesis, because circulating leukocytes were present at normal abundance in both WT and CalpTG mice (supplemental Table II). Rather, it was related to a defect in chemotaxis, as reflected by the lack of MCP-1 release into the abdominal cavity of CalpTG mice (Figure 5e). These results demonstrate that Ang II–dependent perivascular inflammation is strongly reduced in CalpTG mice because of a defect in leukocyte recruitment, which is attributable to a decrease in both the release of and the response to MCP-1.
Prevention of Ang II–Dependent Perivascular Inflammation and Cardiovascular Hypertrophy in CalpTG Mice Is Associated With an Inhibition of NF-B but Not NFAT
NF-B is a central transcription factor involved in Ang II–mediated vascular inflammation/remodeling and cardiac hypertrophy.21,22 Because calpain activity participates in NF-B activation process,12 we considered the possibility that transgene-dependent decrease in calpain activity may result in a reduction of NF-B activation. Infusion of Ang II led to a marked increase in the nuclear expression of NF-B p65 subunit within both kidney cortex and heart of WT mice, and significant blunting of these Ang II–mediated effects was observed in CalpTG mice (Figure 6).
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Similarly, because Ang II–induced cardiac hypertrophy is attenuated in NFAT4 (NFATc3)-null mice23 and because calpains have been shown to activate the calcineurin/NFAT pathway, we compared the nuclear translocation of NFATc3 in the heart of WT and CalpTG mice. Ang II–induced NFATc3 translocation was not modified by the calpastatin transgene (Figure 6). These data suggest that calpain activity is essential for Ang II–induced cardiovascular remodeling through the activation of NF-B but not NFATc3.
Ang II–Dependent Perivascular Fibrosis in WT and CalpTG Mice
Ang II promotes perivascular fibrosis in addition to media hypertrophy and infiltration of mononuclear cells.24 Infusion of Ang II for 4 weeks indeed resulted in robust fibrosis around aorta and kidney interlobular arteries of WT mice, as evidenced by polarized light microscopy analysis of Sirius red staining25 and immunohistochemical analysis of type I collagen. Significant blunting of these Ang II–mediated effects were observed in CalpTG mice (Figure 7a, and 7b, 7e, and 7f). The mechanism by which calpastatin-dependent protection occurs could involve an increase in collagen degradation by MMPs and/or a decrease in collagen deposition. A paradoxical decrease of MMP activity (determined by in situ zymography and quantitative zymography: 3.83±0.89 versus 19.93±1.97 optical density units; N=3; P<0.005) in aortic media of CalpTG mice as compared with WT mice excluded the first hypothesis (Figure 7a and 7d). In contrast, a significant decrease in Ang II–induced synthesis and secretion of collagen in VSMCs from CalpTG mice as compared with WT mice (Figure 7c and supplemental Figure II) indicated that calpain activity promotes perivascular fibrosis partly through a direct effect on collagen production.
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In addition to perivascular fibrosis, kidney interstitial fibrosis was observed after 4 weeks of Ang II infusion in WT mice and, to a much lesser extent, in CalpTG mice (Figure 7g), suggesting that the calpain/calpastatin system is involved in this tissue fibrosis process as well.
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Discussion |
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The novel evidence presented here that calpastatin gene transfer prevents cardiovascular remodeling in Ang II–dependent hypertension suggests that calpains are involved in mechanisms underlying this disorder and may thus represent an attractive therapeutic target. Calpastatin overexpression in all tissues rather than specifically in vascular wall or myocardium,26 although impeding identification of the role of calpains in each of these structures individually, is more appropriate to assess the therapeutic potential of drugs inhibiting calpain activity in all tissues. As determined by measuring the accumulation of calpain-specific spectrin BDP, overexpression of calpastatin did not affect calpain activity under normal conditions; however, this activity was blunted significantly after Ang II perfusion. Recently, we13 and Takano et al27 also observed that basal calpain activity remained unchanged in the tissues (kidney and brain, respectively) of calpastatin transgenic mice as compared with WT controls. It is therefore conceivable that calpastatin controls calpain activity only under pathological conditions. In support of this idea, Pontremoli and colleagues 28 have shown that calpains and calpastatin are not colocalized within the cell at rest. After calcium-related cell stimulation, calpastatin diffusion allows calpastatin to interact with calpains, thereby modulating its activity.
We found that after 4 weeks of infusion with Ang II, WT mice developed a more severe hypertrophy of vascular media than CalpTG mice, the extent of blood pressure elevation being similar in the 2 groups of mice. These results validate the novel concept that calpains are involved in local or tissue renin–angiotensin systems (which cause cardiovascular remodeling) rather than in the circulating renin–angiotensin system (which induces hypertension through vasoconstriction and aldosterone release from the adrenal cortex).29
Vascular remodeling occurs in response to increased arterial blood pressure and/or activation of the renin–angiotensin–aldosterone system.2,3 According to the law of Laplace, 1 option for a vessel to normalize its wall stress in hypertension is to undergo hypertrophy. This hypertrophic remodeling is the consequence of alterations in the growth and/or size of VSMCs and accumulation of extracellular matrix proteins. Our in vivo data show that Ang II–dependent vascular remodeling is limited in both large arteries (aorta) and small kidney arteries from CalpTG mice as compared with WT mice. The difference between the 2 groups of mice reflects differences in the hypertrophic response of VSMCs to Ang II, as demonstrated in vitro by measuring [3H]leucine incorporation. Further pharmacological studies have provided evidence for the molecular mechanisms underlying the response to Ang II. After binding to AT1 receptors, Ang II promoted the transactivation of EGFR, which, in turn, would activate a mitogen-activated protein kinase cascade, resulting in phosphorylation and activation of calpain 2.18,30
Cardiac hypertrophy was also limited in CalpTG mice given Ang II. Basically, transcription factors that are both activated by calpains and responsible for Ang II–dependent left ventricular hypertrophy (reviewed elsewhere31) are potentially involved in this response. Among them, the most important is NF-B. Calpains degrade the inhibitor IB
, a key step in nuclear translocation of NF-B,12 and mice lacking the p50 subunit of NF-B or expressing an NF-B super-repressor show limited cardiac hypertrophy in response to chronic Ang II infusion.22 It is likely that NF-B signaling controls the expression of genes involved in cardiomyocyte hypertrophy (eg, the interleukin-6 receptor gp130). Similarly, calpains activate the serine/threonine protein phosphatase calcineurin via the proteolysis of its autoinihibitory domain, leading to the nuclear translocation of dephosphorylated NFAT in tissues, including heart,32 and NFATc3-null mice have blunted cardiac hypertrophy following Ang II infusion.23 However, based on our results, calpain activity mediates Ang II–dependent left ventricular hypertrophy through a NFATc3-independent process.
In hypertension, small foci of inflammatory cells consisting mainly of lymphocytes and macrophages have been described in both perivascular and tissue interstitial regions, where they precede fibrosis process.33 Calpains may contribute to these events by at least 3 different mechanisms. First, by promoting NF-B activation, calpains may induce both the expression of and the cell response to MCP-1, which recruits lymphocytes and macrophages. Second, by the cleavage of cytoskeletal linkage molecules such as talin and ezrin, calpains are responsible for the extravasation and the migration of leukocytes.9,34 Third, by promoting NF-B activation, calpains may induce the expression of endothelin-1,35 which, in turn, induces vascular inflammatory response through increased oxidative stress and stimulation of proinflammatory cytokines.21 The results reported here suggest an involvement of the first mechanism. The latter mechanism is unlikely, because endothelin-1 gene and protein expression were not altered after 4 weeks of Ang II infusion in CalpTG mice as compared with WT mice (data not shown).
There is evidence of a causal relationship between inflammatory cells and fibrosis, because anti–MCP-1 therapy prevents macrophage accumulation and limits perivascular and interstitial fibrosis in hypertension.36 With regard to the exact mechanisms involved, infiltrating inflammatory cells are capable of releasing numerous cytokines, which may regulate fibroblast recruitment and proliferation. Among them, interleukin-13 and transforming growth factor-β generated by mononuclear cells preferentially stimulate the macrophage activity of arginase-1, which is crucial for fibroblast growth and collagen synthesis.37,38 Thus, calpains may participate in fibrosis process mainly by recruiting inflammatory cells.
Calpain-induced cardiovascular and tissue fibrosis also may result from changes in matrix protein turnover. We observed that calpastatin transgene expression was mirrored paradoxically by a decrease in MMP activity. Thus, the antifibrotic action of calpastatin would be explained by a decrease in collagen deposition rather than an increase in collagen degradation. This hypothesis is consistent with our observation that VSMCs derived from the aorta of CalpTG mice produce much less collagen in response to Ang II.
In summary, the present studies demonstrate that calpains contribute to the development of Ang II–induced cardiovascular remodeling. Specifically, the loss of calpain activation prevents myocardial and vascular hypertrophy, perivascular inflammation, and perivascular or tissue fibrosis. It is interesting to note that this protection is observed even though hypertension remains unchanged. Therefore, our studies have important clinical significance in providing evidence for an alternative strategy in the treatment of cardiovascular remodeling. In support of this option, loss of calpain activation appears to prevent overall consequences of Ang II–induced hypertension, and this protective role is tremendous. Further work is needed to assess the clinical efficacy of available calpain inhibitors, focusing on drugs that increase calpastatin expression, because this strategy appears to limit calpain activation without interfering with basal calpain activity.
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Acknowledgments |
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Sources of Funding
This work was supported by the Institut National de la Santé et de la Recherche Médicale and by the Faculté de Médecine Saint-Antoine. Additional support was provided by grants from the Association pour la Recherche sur le Cancer (grant 9946), the Ligue Nationale contre le Cancer (Comité de Paris), and the Baxter Extramural Grant Program.
Disclosures
None.
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Footnotes |
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Original received July 17, 2007; revision received January 2, 2008; accepted January 24, 2008.
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