Dataset Information

Myocardial Injury Promotes Matrix Metalloproteinase-9 Activity in the Renal Cortex in Preclinical Models of Acute Myocardial Infarction.

ABSTRACT: New mechanistic insight into how the kidney responds to cardiac injury during acute myocardial infarction (AMI) is required. We hypothesized that AMI promotes inflammation and matrix metalloproteinase-9 (MMP9) activity in the kidney and studied the effect of initiating an Impella CP or veno-arterial extracorporeal membrane oxygenation (VA-ECMO) before coronary reperfusion during AMI. Adult male swine were subjected to coronary occlusion and either reperfusion (ischemia-reperfusion; IR) or support with either Impella or VA-ECMO before reperfusion. IR and ECMO increased while Impella reduced levels of MMP-9 in the myocardial infarct zone, circulation, and renal cortex. Compared to IR, Impella reduced myocardial infarct size and urinary KIM-1 levels, but VA-ECMO did not. IR and VA-ECMO increased pro-fibrogenic signaling via transforming growth factor-beta and endoglin in the renal cortex, but Impella did not. These findings identify that AMI increases inflammatory activity in the kidney, which may be attenuated by Impella support.

SUBMITTER: Qiao X

PROVIDER: S-EPMC8983528 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Myocardial Injury Promotes Matrix Metalloproteinase-9 Activity in the Renal Cortex in Preclinical Models of Acute Myocardial Infarction.

Qiao Xiaoying X Bhave Shreyas S Swain Lija L Zweck Elric E Reyelt Lara L Crowley Paige P Annamalai Shiva K SK Chennjorwala Aditya A Esposito Michele M Razavi Allen A Foroutanjazi Sina S Machen Cody C Thayer Katherine K Jorde Lena L Karas Richard H RH Kapur Navin K NK

Journal of cardiovascular translational research 20210329 2

New mechanistic insight into how the kidney responds to cardiac injury during acute myocardial infarction (AMI) is required. We hypothesized that AMI promotes inflammation and matrix metalloproteinase-9 (MMP9) activity in the kidney and studied the effect of initiating an Impella CP or veno-arterial extracorporeal membrane oxygenation (VA-ECMO) before coronary reperfusion during AMI. Adult male swine were subjected to coronary occlusion and either reperfusion (ischemia-reperfusion; IR) or suppor ...[more]

PMID: 33782857

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Project description:Matrix metalloproteinase-9 (MMP-9) is robustly elevated in the first week post-myocardial infarction (MI). Targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-MI by reducing macrophage infiltration and collagen accumulation through increased apoptosis and reduced inflammation. In this study, we used a translational experimental design to determine whether selective MMP-9 inhibition early post-MI would be an effective therapeutic strategy in mice. We enrolled male C57BL/6J mice (3-6months old, n=116) for this study. Mice were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03μg/day) treatment was initiated at 3h post-MI and the mice were sacrificed at day (D) 1 or 7 post-MI. MMP-9i reduced MMP-9 activity by 31±1% at D1 post-MI (p<0.05 vs saline) and did not affect survival or infarct area. Surprisingly, MMP-9i treatment increased infarct wall thinning and worsened cardiac function at D7 post-MI. While MMP-9i enhanced neutrophil infiltration at D1 and macrophage infiltration at D7 post-MI, CD36 levels were lower in MMP-9i compared to saline, signifying reduced phagocytic potential per macrophage. Escalation and prolongation of the inflammatory response at D7 post-MI in the MMP-9i group was evident by increased expression of 18 pro-inflammatory cytokines (all p<0.05). MMP-9i reduced cleaved caspase 3 levels at D7 post-MI, consistent with reduced apoptosis and defective inflammation resolution. Because MMP-9i effects on inflammatory cells were significantly different from previously observed MMP-9 null mechanisms, we evaluated pre-MI (baseline) systemic differences between C57BL/6J and MMP-9 null plasma. By mass spectrometry, 34 plasma proteins were significantly different between groups, revealing a previously unappreciated altered baseline environment pre-MI when MMP-9 was deleted. In conclusion, early MMP-9 inhibition delayed inflammation resolution and exacerbated cardiac dysfunction, highlighting the importance of using translational approaches in mice.

Dataset Information

Myocardial Injury Promotes Matrix Metalloproteinase-9 Activity in the Renal Cortex in Preclinical Models of Acute Myocardial Infarction.

Publications

Myocardial Injury Promotes Matrix Metalloproteinase-9 Activity in the Renal Cortex in Preclinical Models of Acute Myocardial Infarction.

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