Elevated levels of homocysteine downregulated CBS but upregulated CSE whereas H2S downregulated CSE but upregulated CBS in cardiomyocytes, indicating the negative feedback between CBS and CSE, which can be influenced by hyperhomocysteinemia or H2S. The direct regulation of CSE by CBS was further confirmed in CBS-deficient hyperhomocysteinemic animals. The gene discussed is CBS; the disease is hyperhomocysteinemia.