CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 1, January – April 2024 AFRICA 55 (MAPK) signalling, calcineurin pathway and signal transducer and activator of transcription 3 (STAT 3) signalling. These pathways lead to gene expression that determines cellular proliferation, hypertrophy, apoptosis differentiation and angiogenesis.51-53 Cardiovascular complications occur as a consequence of cardiac maladaptation during pregnancy.39,54,55 These complications manifest clinically as metabolic changes that occur in gestational diabetes, PE and gestational hypertension and functional changes that occur in peripartum cardiomyopathy.39,56 These conditions lead to cardiac dysfunction and promote the development of heart failure.39,57 This review focuses on cardiac maladaptation associated with PE. PE has been associated with a decrease in cardiac output that corresponds to an increase in systemic vascular resistance.58 The perturbation in haemodynamics is attributed to increased sympathetic innervation, enhanced response to angiotensin II, increased catecholamine release, an imbalance of pro- and anti-angiogenic factors, endothelial dysfunction leading to vasoconstriction, increased systemic vascular resistance and increased left ventricular afterload.58,59 This afterload mismatch in turn results in increased stroke work and myocardial ischaemia, impaired myocardial relaxation and diastolic filling.58 There is a phenotypic heterogeneity of PE: severity of cardiac disease, progression to heart failure and pulmonary oedema, which are determined by genetics, epigenetics and pre-existing cardiovascular dysfunction.58 Systematic reviews of genetic risk factors showed that plasminogen activator inhibitor-1 (PAI-I) and FMS-related tyrosine kinase were associated with PE and are known to be associated with risks of coronary artery disease and heart failure.12 There is also a role of exosomes causing endothelial dysfunction and contributing to cardiovascular disease. Interestingly, there is a plethora of data underscoring the role of altered microRNA expression in pregnancies complicated by cardiovascular disease.39,60 MicroRNAs (miRNAs) are non-coding RNAs that influence gene expression through posttranslational modification by binding to the 3′ untranslated region (3′ UTR) of the target mRNA, leading to premature degradation or prevention of translation.39,61 Upregulated miRNAs in PE Several studies have shown elevated levels of both miR-2103p and miR-210-5p in PE.39,62 MiR-210, a hypoxia-activated miRNA, is upregulated in pathological cardiac hypertrophy and cardiac failure.39,63 Interestingly, it seems to be cardioprotective; in cardiomyocytes, Akt signalling was found to increase miR-210 expression, leading to decreased oxidative stress and cell death, likely through the programmed cell death protein 4 (PDCD4) pathway.39,64 In addition, miR-210 inhibits cell cycle inhibitor adenomatous polyposis coli (APC), and miR-210-expressing female mice demonstrated reduced cardiomyocyte apoptosis, increased angiogenesis and improvement in cardiac function following myocardial infarction (MI).39,65 Similarly, in exosomederived miR-210, which inhibits the angiogenesis modulator ephrin A3, cardiac angiogenesis was promoted following MI in male mice.39,66 MiR-29a is upregulated in mild PE compared to controls and was found to have a dual role in cardiac failure.39,67,68 In patients with hypertrophic cardiomyopathy, plasma miR-29a was found to be increased and correlated positively with both cardiac hypertrophy and fibrosis.39,69 However, miR-29a demonstrated protection against phenylephrine-induced cardiomyocyte hypertrophy through directly stimulating the pro-hypertrophic NFATc4.39,70 Levels of miRNA may vary depending on the severity of disease. MiR-21 and MiR-155 were found to be elevated five- to eight-fold in severe PE compared to mild PE.39,62 Increased miRNA expression has been noted to cause cardiomyocyte hypertrophy. It inhibits sprout homolog 1 (Spry 1) in cardiac fibroblasts and enhances extracellular signal-regulated kinase (ERK) MAPK signalling, leading to cardiac fibrosis and cardiomyocyte hypertrophy.39,71 MiR-21 also stimulates fibrosis following MI in male mice through targeting small mothers against decapentaplegic 7 (SMAD 7), a negative regulator of the TGF-β1 pathway.39,72 However, cardioprotective effects have been demonstrated in a rat model: miR-21 prevented cardiomyocyte apoptosis by targeting PDCD4,39,73 suggesting inherent pleiotropy of the signalling mechanisms of these pathways.39,74,75 Of significance, differences in miRNA expression before clinical onset may be predictive of the development of PE. Plasma miR-206 was upregulated in the early third trimester in asymptomatic patients who later developed PE, in contrast to healthy pregnant patients.39,76 In male mice, miR-206 was demonstrated to stimulate cardiac hypertrophy by targeting tumour suppressor Forkhead box protein 1.39,77 Whether or not miR-206 is expressed at the time of disease onset remains to be investigated. Downregulated miRNAs in PE Various studies have shown plasma and serum levels of miR-144 to be downregulated in PE patients compared to controls in different stages of disease.39,62 Loss of miR-144 signalling in male mice was noted to lead to impaired extracellular matrix remodelling following an MI, resulting in cardiac dysfunction. MiR-144 targets zinc finger E box binding homeobox 1 (Zeb 1), a mediator of mesenchymal transition and a profibrotic response following an insult.39,78 In addition, loss of miR-144 in male mice enhances injury following an MI by targeting Ras-related c3 botulinum toxin substrate 1 (Rac1), a major component of NADPH oxidase, leading to generation of ROS and oxidative damage.39,79 MiR-125b-5p andmiR-195-5pwere found to be downregulated in severe PE compared to controls. However, elevated levels of miR-195-5p have also been described and shown to correlate positively with sFlt-1 levels.39,80 In male mice, miR-195-5P stimulates angiotensin II-induced cardiomyocyte hypertrophy through downstream signalling: it targets tumour suppressor FBXW7 and mitofusin 2 (MFN 2), which inhibit mitochondrial membrane depolarisation and generation of ROS.39,81 Differential expression of miRNA levels prior to clinical onset could be predictive of disease development. Serum levels of miR-126, miR-204 and miR-15b in early gestation were found to be decreased in patients who developed severe PE in the third trimester, in contrast to patients who developed a healthy pregnancy.39,82 MiR-126 plays a role in endothelial cell integrity as it represses anti-angiogenic modulator sprouty related, EVH1 domain-containing protein 1 (Spred 1), resulting in abnormal
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