Cardiovascular diseases (CVDs) are the leader global cause of death. Cell organelles determines cells fate in CVDs. Here we studied the regulatory effects of non-coding RNAs on function and crosstalk among cell organelles especially in endoplasmic reticulum (ER) and mitochondria in different CVDs. In mitochondria, we found mitomiR-4485-3p and lncRNA MIAT impaired myocardial infarction (MI) by inducing cardiomyocytes apoptosis. MitomiR-4485-3p released to cytosol in response to injury in MI, which targeted PPARα and induced dysregulation of mitochondrial energy metabolism and apoptosis in cardiomyocytes. In addition, lncRNA MIAT induces cardiomyocytes apoptosis and impairs cardiac contractile function by acting on mitochondrial translocator protein TSPO in MI. In ER, we identified lncRNA ZFAS1 as a regulator of calcium homeostasis in a mouse model of pressure-overload HF. We found that circulating level of lncRNA ZFAS1 was significantly lower in MI than in non-MI patients. Then we revealed lncRNA-ZFAS1 as a natural inhibitor of SERCA2a by binding to SERCA2a protein. Abnormally increased ZFAS1 in MI significantly impaired cardiac function. Most prominently, we identified a region of high degree conservation across man and mouse species named functional sequence domain of ZFAS1, which is much shorter and responsible for its deleterious effects. Our study identified functional non-coding RNAs as network hub of organelles in CVDs, which provides potential therapeutic agents for ameliorating cardiac dysfunction.