Doxycycline Dose‐dependently Inhibits MMP‐2‐Mediated Vascular Changes in 2K1C Hypertension

Abstract

Hypertension induces vascular alterations that are associated with up-regulation of matrix metalloproteinases (MMPs). While these alterations may be blunted by doxycycline, a non-selective MMPs inhibitor, no previous study has examined the effects of different doses of doxycycline on these alterations. This is important because doxycycline has been used at sub-antimicrobial doses, and the use of lower doses may prevent the emergence of antibiotic-resistant microorganisms. We studied the effects of doxycycline at 3, 10 and 30 mg ⁄ kg per day on the vascular alterations found in the rat two kidneyone clip (2K1C) hypertension (n = 20 rats ⁄ group). Systolic blood pressure (SBP) was monitored during 4 weeks of treatment.We assessed endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall was studied, and aortic MMP-2 levels ⁄ proteolytic activity were determined by gelatin and in situ zymography, respectively. All treatments attenuated the increases in SBP in hypertensive rats (195.4 € 3.9 versus 177.2 € 6.2, 176.3 € 4.5, and 173 € 5.1 mmHg in 2K1C hypertensive rats treated with vehicle, or doxycycline at 3, 10, 30 mg ⁄ kg per day, respectively (all p < 0.01). However, only the highest dose prevented 2K1C-induced reduction in endothelium-dependent vasorelaxation (p < 0.05), vascular hypertrophy and increases in MMP-2 levels (all p < 0.05). In conclusion, our results suggest that relatively lower doses of doxycycline do not attenuate the vascular alterations found in the 2K1C hypertension model, and only the highest dose of doxycycline affects MMPs and vascular structure. Our results support the idea that the effects of doxycycline on MMP-2 and vascular structure are pressure independent.Hypertension is a major cardiovascular disease that is associated with vascular remodelling characterized by degradation and reorganization of extracellular matrix in the vessel wall [1]. Vascular remodelling is an adaptive response to elevation of arterial pressure to normalize the wall tension [2] and has been clearly described in experimental models of hypertension, including the 2-kidney, 1-clip (2K1C) Goldblatt model, which involves the activation of the renin-angiotensin-aldosterone axis [3,4].Metalloproteinases (MMPs) are zinc-containing enzymes that play important roles in cardiovascular diseases [5]. Upregulated MMPs promote excessive degradation of extracellular matrix and are involved in pathological vascular remodelling [6], which includes vascular smooth muscle cell migration and proliferation in the arterial wall [7]. In fact, increased expression and activity of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) have been consistently implicated in vascular remodelling associated with hypertension in patients [8,9] and animal models [10][11][12][13][14][15][16]. We have recently found evidence suggesting that enhanced aortic MMP-2 levels and activity may underlie the impaired endothelial-dependent vasorelaxation, arterial wall hypertrophy, and excessive c...

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

“…It is also affected by a variety of signalling molecules, particularly MMP-2. Indeed, we have previously shown that some antihypertensive drugs did not reverse 2K1C hypertension-induced vascular remodelling, unless MMP-2 inhibition was also present [26,34]. These findings support the suggestion that the antiremodelling effects of PDTC reported here are due to its inhibitory effects on MMP-2 expression.…”

Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

“…These metalloproteinases, when activated, cleave and release (shed) growth factors (e.g., HB-EGF) and cytokines (e.g., TNF-α), leading to the activation of their cognate receptors and downstream signaling involving MAPKs, PI3K-Akt and ROS. Studies using animal models have shown that non-specific inhibition of metalloproteinases can attenuate the development of systemic and pulmonary hypertension, cardiac hypertrophy and vascular remodeling, confirming the significance of metalloproteinases in these cardiovascular diseases (172)(173)(174)(175).…”

“…The emergence of metalloproteinases as common mediators of multiple agonists makes them candidate therapeutic targets for the treatment of hypertensive cardiac disease in these conditions. In support of this notion, the inhibition of specific metalloproteinases has been shown to ameliorate the development of cardiovascular disease in various animal models (172)(173)(174)(175) Postulated model whereby GPCR agonists signal hypertension and pathological cardiovascular remodeling through induction of contraction and gene expression in vasculature and the heart. GPCR: G protein-coupled receptor.…”

“…The metalloproteinase inhibitor CMT-3 has demonstrated dramatic improvement in the tumor burden of patients with Kaposi Sarcoma in clinical trials (266,267). Other metalloproteinase inhibitors, including GM6001, batimastat and marimastat have also proven effective in experimental disease models, however success has also been limited in the clinical trials (177,(268)(269)(270)(271)(272). The synthetic MMP inhibitor PG-116800 failed to improve any clinical outcomes and showed no reduction in myocardial infarction-induced ventricular remodeling in post-myocardial infarction patients (273).…”

Effect of All-Trans Retinoic Acid (ATRA) against expression of Matrix Metalloproteinase-2 (MMP-2) in model mice (Rattus norvegicus) periodontitis

“…The expression and the activity of this enzyme are predictive indicators for periodontitis condition. 4 Today many kind of efforts have been developed to act against that MMP enzyme activity. One that is alleged to inhibit MMP activities is vitamin A metabolite.…”