Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
J Appl Physiol (1985). 2011 Apr;110(4):1093-100. doi: 10.1152/japplphysiol.01064.2010. Epub 2011 Jan 13.
We reported previously that although there is disruption of coordinated cardiac hypertrophy and angiogenesis in transition to heart failure, matrix metalloproteinase (MMP)-9 induced antiangiogenic factors play a vital role in this process. Previous studies have shown the cardioprotective role of hydrogen sulfide (H₂S) in various cardiac diseases, but its role during transition from compensatory hypertrophy to heart failure is yet to be unveiled. We hypothesize that H₂S induces MMP-2 activation and inhibits MMP-9 activation, thus promoting angiogenesis, and mitigates transition from compensatory cardiac hypertrophy to heart failure. To verify this, aortic banding (AB) was created to mimic pressure overload in wild-type (WT) mice, which were treated with sodium hydrosulfide (NaHS, H₂S donor) in drinking water and compared with untreated control mice. Mice were studied at 3 and 8 wk. In the NaHS-treated AB 8 wk group, the expression of MMP-2, CD31, and VEGF was increased while the expression of MMP-9, endostatin, angiostatin, and tissue inhibitor of matrix metalloproteinase (TIMP)-3 was decreased compared with untreated control mice. There was significant reduction in fibrosis in NaHS-treated groups. Echocardiograph and pressure-volume data revealed improvement of cardiac function in NaHS-treated groups over untreated controls. These results show that H₂S by inducing MMP-2 promotes VEGF synthesis and angiogenesis while it suppresses MMP-9 and TIMP-3 levels, inhibits antiangiogenic factors, reduces intracardiac fibrosis, and mitigates transition from compensatory hypertrophy to heart failure.
我们之前曾报道，尽管在向心力衰竭过渡时存在协调的心脏肥大和血管生成的破坏，但基质金属蛋白酶（MMP）-9 诱导的抗血管生成因子在这一过程中起着至关重要的作用。先前的研究表明，硫化氢（H₂S）在各种心脏疾病中具有心脏保护作用，但它在从代偿性肥大向心力衰竭过渡过程中的作用尚未被揭示。我们假设 H₂S 诱导 MMP-2 激活并抑制 MMP-9 激活，从而促进血管生成，并减轻从代偿性心肌肥厚向心力衰竭的过渡。为了验证这一点，我们通过主动脉缩窄（AB）在野生型（WT）小鼠中模拟压力超负荷，并用饮用水中的硫氢化钠（NaHS，H₂S 供体）处理这些小鼠，并与未处理的对照组小鼠进行比较。在第 3 周和第 8 周对这些小鼠进行了研究。在 NaHS 处理的 AB 8 周组中，与未处理的对照组小鼠相比，MMP-2、CD31 和 VEGF 的表达增加，而 MMP-9、内皮抑素、血管生成抑制素和基质金属蛋白酶组织抑制剂（TIMP）-3 的表达减少。在 NaHS 处理组中，纤维化明显减少。超声心动图和压力-容积数据显示，与未处理的对照组相比，NaHS 处理组的心脏功能得到了改善。这些结果表明，H₂S 通过诱导 MMP-2 促进 VEGF 合成和血管生成，同时抑制 MMP-9 和 TIMP-3 水平，抑制抗血管生成因子，减少心脏内纤维化，并减轻从代偿性肥大向心力衰竭的过渡。
