## 6 LncRNAs and Cardiovascular Disease
### Roles of LncRNAs in Myocardial Infarction  
Sudden cardiac death accounts for approximately 50% of all heart-related death in the United States. Coronary artery disease is the most prevalent cause of sudden cardiac death and is commonly followed by acute myocardial infarction (AMI) if not treated [54]. Coronary artery disease accounts for 22% of early deaths and 15% of late deaths in individuals with cardiovascular disease [55]. It is known that coronary artery disease is featured by the transcriptional reprogramming, which activates a network of cardiac signals that interact and converge on cardiac transcription factors such as serum response factor (SRF), NKX2.5, myocyte-specific enhancer factor 2C (MEF2C), GATA binding protein 4 (GATA4), and TBX3. These transcriptional factors collectively activate specific temporal and spatial programs to generate cardiac pathological remodeling that is controlled by lncRNAs. For example, conditions such as anoxia/re-oxygenation (A/R) and ischemia/reperfusion (I/R) increase the transcription of lncRNA autophagy-promoting factor (APF) [48]. In a study conducted by [PERSON] _et al._, APF was discovered to exacerbate myocardial infarction (MI) injury by interacting with miR-188-3p. MiR-188-3p suppresses the expression of ATG7, a key regulator of autophagy that is known to be crucial in regulating cell death and survival in MI [48]. Multiple lines of evidence were provided to prove that APF modulates MI injury through the inhibition of miR-188-3p. For instance, ATG7 was significantly decreased in the presence of miR-188-3p and knockdown of miR-188-3p resulted in increased levels of endogenous ATG7 expression. However, knockdown of APF in cardiomyocytes showed decreased ATG7 expression. Overall, these data suggest that miR-188-3p is indeed a target of APF and that both miR-188-3p and APF may play important roles in the modulation of ATG7 levels during MI [48]. Furthermore, a microarray-based study showed that MI is associated with the upregulation of MI-associated transcript 1 and 2 (MIRT1 and MIRT2) [49]. An lncRNA MI-associated transcript (MIAT) was also identified as a novel non-coding RNA that regulates MI. LncRNA MIAT is involved in pathological angiogenesis and is suggested as a predictor of MI because MIAT was measured in peripheral blood cells and proposed as a significant invariable predictor of MI (Table 1 and Figure 3) [47]. Recent studies have utilized an advanced technology called SNP Array to identify disease-associated SNPs on a genome-wide scale [47,56]. In a study used 52,608 haplotype-base SNP markers from 3435 MI patients and 3774 controls, several SNPs were linked to non-coding regions of the genome, which produced no translational protein product _in vitro_[47]. The findings of the study revealed six SNPs on chromosome 22q12.1 that had significant association with MI. Within the locus, authors identified a lncRNA MIAT, which has five exons and is 10 kb in length [47]. Overall, the study suggests that the change in MIAT expression by the SNPs is involved in the pathogenesis of MI. Additionally, genome-wide association studies have revealed regions on chromosome 9p that are associated with coronary artery disease [57]. An antisense lncRNA called ANRIL has been found in the LNK4 locus and several SNPs in the ANRIL locus on chromosome 9p are involved in coronary artery disease and diabetes (Table 1 and Figure 3) [43]. Several studies also have linked ANRIL in increasing the risks of intracranial aneurysm [58], breast cancer [59], glioma [60], and basal cell carcinoma [61]. Further studies have also proven an association between MI and lncRNAs. In a microarray-based study, it was found that 20 lncRNAs were up-regulated and 10 lncRNAs were down-regulated following MI in mice. It was noted that among the 30 lncRNAs, two specific lncRNAs, MIRT1 and MIRT2, were significantly up-regulated by 5-fold and 13-fold, respectively. MIRT1 and MIRT2 were associated with genes involved in left ventricular remodeling [49].