Cardiac‐specific overexpression of metallothionein attenuates L‐NAME‐induced myocardial contractile anomalies and apoptosis

Abstract

Hypertension contributes to the high cardiac morbidity and mortality. Although oxidative stress plays an essential role in hypertensive heart diseases, the mechanism remains elusive. Transgenic mice with cardiac overexpression of metallothionein, a heavy metal‐binding scavenger, were challenged with N G ‐nitro‐L‐arginine methyl ester (L‐NAME) for 14 days prior to measurement of myocardial contractile and intracellular Ca 2+ anomalies as well as cell signalling mechanisms using Western blot and immunofluorescence analysis. L‐NAME challenge elicited hypertension, macrophage infiltration, oxidative stress, inflammation and cardiac dysfunction manifested as increased proinflammatory macrophage marker F4/80, interleukin‐1β (IL‐1β), intracellular production, LV end systolic and diastolic diameters as well as depressed fractional shortening. L‐NAME treatment reduced mitochondrial membrane potential (MMP), impaired cardiomyocyte contractile and intracellular Ca 2+ properties as evidenced by suppressed peak shortening, maximal velocity of shortening/relengthening, rise in intracellular Ca 2+ , along with elevated baseline and peak intracellular Ca 2+ . These unfavourable mechanical changes and decreased MMP (except blood pressure and macrophage infiltration) were alleviated by overexpression of metallothionein. Furthermore, the apoptosis markers including BAD, Bax, Caspase 9, Caspase 12 and cleaved Caspase 3 were up‐regulated while the anti‐apoptotic marker Bcl‐2 was decreased by L‐NAME treatment. Metallothionein transgene reversed L‐NAME‐induced changes in Bax, Bcl‐2, BAD phosphorylation, Caspase 9, Caspase 12 and cleaved Caspase 3. Our results suggest that metallothionein protects against L‐NAME‐induced myocardial contractile anomalies in part through inhibition of apoptosis.

Unraveling the Mystery of Cold Stress-Induced Myocardial Injury

“…Some studies have revealed the role of oxidative stress in myocardial injury caused by cold stress through antioxidants. Metallothionein, a low molecular weight heavy metal-chelating antioxidant (Yang et al, 2019), significantly improves ROS overproduction, myocardial fibrosis, and myocardial contraction dysfunction caused by cold stress (Zhang et al, 2012a).…”

Association of zinc level with DNA methylation and its consequences: A systematic review

“…Likewise, the liver of offspring from zinc-deficient pregnant mice showed hypermethylation in the -820 CpG region of the MT2 gene but no methylation in the -480 to +140 region of this gene which contains metal responsive elements (MREs) [ 17 ]. MT has been shown to engage in heavy metal ions, such as zinc and copper transport, metabolism and homeostasis in tissue and cells [ 47 ]. MT methylation intensity was shown to be linked with the downregulation of gene expression [ 48 ].…”

MiR-490-5p Restrains Progression of Gastric cancer through DTL Repression

“…It is reported that miR-490 also decreases in esophageal cancer, pancreatic cancer and other digestive cancers [ 29 ]. According to Li and other colleagues, miR-490-5p upregulation leads to inhibition on proliferation and induction on cell cycle arrest in G0/G1 phase in bladder cancer [ 30 ]. We illustrated that miR-490-5p exerted a similar effect in GC, which hindered malignant progression of the disease.…”