Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis.

Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.

Molecular mechanisms of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin.

Carfilzomib (Cfz), an irreversible proteasome inhibitor licensed for relapsed/refractory myeloma, is associated with cardiotoxicity in humans. We sought to establish the optimal protocol of Cfz-induced cardiac dysfunction, to investigate the underlying molecular-signaling and, based on the findings, to evaluate the cardioprotective potency of metformin (Met). Mice were randomized into protocols 1 and 2 (control and Cfz for 1 and 2 consecutive days, respectively); protocols 3 and 4 (control and alternate doses of Cfz for 6 and 14 days, respectively); protocols 5A and 5B (control and Cfz, intermittent doses on days 0, 1 [5A] and 0, 1, 7, and 8 [5B] for 13 days); protocols 6A and 6B (pharmacological intervention; control, Cfz, Cfz+Met and Met for 2 and 6 days, respectively); and protocol 7 (bortezomib). Cfz was administered at 8 mg/kg (IP) and Met at 140 mg/kg (per os). Cfz resulted in significant reduction of proteasomal activity in heart and peripheral blood mononuclear cells in all protocols except protocols 5A and 5B. Echocardiography demonstrated that Cfz led to a significant fractional shortening (FS) depression in protocols 2 and 3, a borderline dysfunction in protocols 1 and 4, and had no detrimental effect on protocols 5A and 5B. Molecular analysis revealed that Cfz inhibited AMPKα/mTORC1 pathways derived from increased PP2A activity in protocol 2, whereas it additionally inhibited phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathway in protocol 3. Coadministration of Met prevented Cfz-induced FS reduction and restored AMPKα phosphorylation and autophagic signaling. Conclusively, Cfz decreased left ventricular function through increased PP2A activity and inhibition of AMPKα and its downstream autophagic targets, whereas Met represents a novel promising intervention against Cfz-induced cardiotoxicity.