Hydrogen sulfide mitigates transition from compensatory hypertrophy to heart failure

Abstract

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.

Role of Cystathionineγ-Lyase/Hydrogen Sulfide Pathway in Cardiovascular Disease: A Novel Therapeutic Strategy?

“…The effects of H 2 S have been attributed to an increase in VEGF expression in the skeletal muscles and VEGFR2 phosphorylation in the neighboring vascular endothelial cells (59). Consistent with the effects of H 2 S in hindlimb ischemia, a recent study (16) reported on the angiogenic effect of H 2 S treatment in myocardial hypertrophy. After H 2 S treatment in an aortic banding-induced pressure-overload mouse model, functional and histological evaluations performed 3 and 8 weeks later revealed that H 2 S supplementation improved cardiac function and the response was associated with a significant increase in capillary density, which mitigated transition from compensatory hypertrophy to heart failure (16).…”

“…However, as observed by Papapetropoulos et al (48), although H 2 S activates the Akt pathway, it is the MAPK (ERK1/2 and p38) and ATP-sensitive potassium (K ATP ) channel opening pathways, not the Akt pathway, that are involved in H 2 S-stimulated angiogenesis. Consistently, however, H 2 S is reported to mediate angiogenesis through regulation of anti-angiogenic/angiogenic factors production by regulating the matrix metalloproteinase/tissue inhibitor of metalloproteinase axis (16) (Fig. 4).…”

Predictive Value of Endostatin in Chronic Heart Failure Patients with Poor Kidney Function

“…The findings in patients with a low eGFR is reminiscent of the association between higher levels of endostatin and worse outcomes in patients with progressive renal disorders [5,6], potentially reflecting the ability of endostatin to attenuate repair processes after ischemic injury [4,11]. Similarly, endostatin has been suggested to decrease blood supply to the hypertrophied myocardium leading to collagen deposition and fibrosis during experimental HF [12,13]. In contrast, the finding of an association between higher endostatin and better outcomes in patients with preserved renal function could suggest this biological factor may have beneficial effects in some circumstances.…”

Discoveries of Hydrogen Sulfide as a Novel Cardiovascular Therapeutic

“…41 Additionally, administration of NaHS in drinking water increased VEGF expression and inhibited angiostatin and endostatin, 2 antiangiogenic factors. 42 Also, the upregulation of both Akt and VEGF may cause this evident angiogenesis phenotype after administration with a H2S donor molecule (SG-1002). 5 H2S also modulates cellular homeostasis by affecting mito- …”